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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
Department of Pharmacology
Honours Projects 2014
www.monash.edu
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
Welcome to the Pharmacology Department! The Honours year represents a new adventure, very different to your undergraduate experience, in which you will have the opportunity to undertake a research project, communicate your science to colleagues and peers and learn to critically evaluate scientific concepts and literature. Your supervisor(s) will be there to guide and advise you along this research journey. At the very least, you are expected to bring with you the following skills set, in no particular order: -enthusiasm -an enquiring mind -respect & humility -determination & persistence -a sense of humour -a collegial spirit -patience This booklet provides information about the research projects on offer in the Department of Pharmacology and we encourage you to identify the areas of research in which you are most interested, contact potential supervisors and discuss the projects with them. The course convenors, A/Prof Grant Drummond and Dr Barb Kemp-Harper, can advise on projects, guide you through the application process and help with any queries you may have. We look forward to welcoming you the Department of Pharmacology in 2014 and wish you all the best for a rewarding and exciting year of research. Good luck!
Professor Robert Widdop Head, Department of Pharmacology
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
Department of Pharmacology Honours Convenors
Dr Barb Kemp-Harper A/Prof Grant Drummond
Email: [email protected] Email: [email protected]
Phone: 9905 4674 Phone: 9905 4869
Pharmacology Honours: Pre-requisites
BSc Biomedicine BBiotech BBNS BMS
Pre-requisites A Distinction average (>70) in 24 points at 3
rd year in relevant
disciplines within the School of Biomedical Sciences*
A Distinction average (>70) in 24 points at 3
rd year level,
including BTH3012
A Distinction average (>70) in 24 points at 3
rd year
level, including at least 18 points in 3
rd year PHA units
A Distinction average (>70) in 24 points at 3
rd year level,
including 12 points in 3
rd year core BMS
units and 12 points in other 3
rd year units*
Application closing date
15th
November 2013 15th
November 2013 31st
October 2013 15th
November 2013
Application form http://monash.edu/science/current/honours/how-to-apply/
http://monash.edu/science/current/honours/how-to-apply/
http://www.med.monash.edu.au/psych/course/4thyear/bbns-honours-apply.html
www.med.monash.edu/biomed/honours/
Commencement date
24th February, 2014 24
th February, 2014 24
th February, 2014 24
th February, 2014
* There is no pre-requisite in terms of 3
rd year PHA units, but the Pharmacology Honours Convenors
will need to be satisfied that you have the necessary background in pharmacology to undertake your
chosen research project.
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
Pharmacology Honours Course
The Pharmacology BSc Biomedicine Honours Course comprises 2 units:
BMH4100 (36 points) Research Unit
BMH4200 (12 points) Coursework Unit
BMH4100 This major focus of this unit is the research project you will conduct under the guidance of
your supervisor. The assessment tasks include:
Literature Review
Research Seminars (introductory & final)
Thesis & its defence
BMH4200 This unit provides you with the necessary skills to critically review and evaluate the scientific
literature and effectively communicate concepts related to the discipline of pharmacology
and your research area both in writing and orally. The assessment tasks include:
Journal club presentation & participation
Assessment of data exam
Written critique of scientific paper exam
Assessment of scientific writing
Bachelor of Biomedical Science (BMS) Honours students undertake
BMS4100 (identical to BMH4100)
BMS4200 (similar to BMH4200 but administered through the School of Biomedical
Sciences)
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
Choosing an Honours Project
The research projects on offer in the Department of Pharmacology and off-campus, with our
collaborators, are outlined in the following pages. Once you have identified a few projects
that you find interesting, then contact the potential supervisors by email or phone and
arrange to meet with them to find out more about the projects on offer. Its a great idea to
visit the research labs and meet other members of the research group in order to get a feel
for the people you would be working with and type of research you would be undertaking.
Please note that the availability of a supervisor to sign you on for a project will depend on
that project still being available and the limit as to how many students a supervisor can take
on. At least one of your supervisors must be a member of staff or an adjunct member of
staff of the Department of Pharmacology.
How do I apply?
Once you, together with your potential supervisor, have identified a project that would be
suitable for your Honours research program, then you will need to complete the application
form from the specific faculty you are from (i.e. Faculty of Science Website for BSc students
and Faculty of Medicine Website for BMS students). These forms must be signed by one of
the Honours Convenors of the Pharmacology Department (Dr Barb Kemp-Harper or A/Prof
Grant Drummond).
Students enrolling through the Faculty of Science must go to the Faculty of Science office for
an eligibility check to ensure that they are/will be eligible to commence the relevant Honours
program in Semester 1, 2014. Students must obtain this eligibility check before they go to the
Honours coordinator to get their form signed.
Application forms must be submitted by Friday 15th November to:
Science Faculty Office (BSc, BBiotech students)
SOBS Office, Building 77 (BMS students)
For Bachelor of Behavioural Neuroscience Honours students, application forms must be
submitted by Thursday October 31st to:
Emily Cavanagh, School of Psychology & Psychiatry, Building 17
All applications will be reviewed and students who meet the eligibility criteria will be informed
of their success in obtaining an Honours place by letter, which will be sent out in mid
December 2013. Students must then notify the Faculty and supervisor of their intention to
accept or reject the place. Students will be able to enrol into the Honours course via WES in
January 2014.
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
Honour Projects 2014 On campus projects
LABS / SUPERVISOR(S)
PROJECT TITLE
Clinical & Experimental Toxicology Group Andis Graudins, Dimitri Gerostamoulos
The effects of the timing of intravenous lipid emulsion administration on absorption and bioavailability of orally administered lipophilic toxicants in a rodent model of oral amitriptyline toxicity
Education-based projects Eva Patak, Liz Davis
Evaluation & development of web-based pharmacology resources
Fibrosis Group Chrishan Samuel, Simon Royce
Investigating novel anti-fibrotic therapies Integrative Cardiovascular Pharmacology Group Tracey Gaspari, Rob Widdop Claudia McCarthy, Rob Widdop Emma Jones, Mark Del Borgo, Rob Widdop Sanjaya Kuruppu (Biochemistry), Rob Widdop
Cardio-protective effects of incretin hormones: potential beyond glycaemic control?
Inhibition of acid sensing ion channels (ASIC) as a novel treatment for stroke
Drug discovery program for AT2 receptor ligands
Predicting complications associated with haemorrhagic stroke
Cardiovascular Immunology Group Antony Vinh
Mechanisms of inflammation and immunity during the development of hypertension
Neuropharmacology Group Richard Loiacono, Siew Yeen Chai (Physiology)
Modulation of neuronal oxytocin effects on social behaviour
Vascular Biology & Immunopharmacology Group Brad Broughton, Chris Sobey Barb Kemp-Harper Barb Kemp-Harper, Grant Drummond Helena Kim, Chris Sobey Sophocles Chrissobolis, Chris Sobey
Are the adverse effects of hormone replacement therapy on stroke outcome mediated by G protein-coupled estrogen receptor signalling?
Exploring the vasoprotective actions of novel HNO donors
Exploring the role of NOX5 in vascular function
Inflammatory mechanisms in ischaemic stroke
Investigating the role of aldosterone in promoting inflammation during atherosclerosis
Oxidant and Inflammation Biology Group Stavros Selemidis
Investigations into the roles of NAPDH oxidases in Influenza A virus indcued lung injury
Venoms & Toxins Group Sanjaya Kruppu, Wayne Hodgson Oded Kleifeld, Sanjaya Kuruppu, Wayne Hodgson
Muscle damage induced by African Puff Adder Venom
Development of proteomic system-wise approach for characterization of snake venoms
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
Honour Projects 2014 Off campus projects
LABS / SUPERVISOR(S)
PROJECT TITLE
Australian Centre for Blood Diseases Justin Hamilton, Grant Drummond
Targeting the human platelet thrombin receptor, PAR4, as a novel anti-thrombotic therapy
Developing isoform-specific PI3K inhibitors as novel anti-platelet agents
Baker IDI Heart & Diabetes Institute Rebecca Ritchie, Barb Kemp-Harper Jennifer Irvine, Karen Andrews, Barb Kemp-Harper Geoffrey Head
Strategies to rescue diabetes-induced heart failure
Nitroxyl protects against the causes of heart failure
Annexin-A1 protects against cardiac inflammation
Effects of positive allosteric modulator of GABAA receptors on hypertension and stress
Central mechanisms in the control of blood pressure
Centre For Eye Research Australia Hitesh Peshavariya, Grant Drummond
Targeting NADPH oxidase using pharmacological inhibitors for treatment of ocular neovascularisation
Department of Forensic Medicine Dimitri Gerostamoulos, Jennifer Pilgrim
The use of dried blood spots (DBS) in forensic toxicology
Drug Discovery Biology Theme Monash Institute of Pharmaceutical Sciences Katie Leach Karen Gregory, Arthur Christopoulos Nigel Bunnett, Bill Graham, Nicholas Barlow
Nigel Bunnett, Chris Porter Nigel Bunnett, Dane Jensen Nigel Bunnett, TinaMarie Lieu Nigel Bunnett, Meri Canals, Daniel Poole Nigel Bunnett, Nicholas Barlow Nigel Bunnett, Paul Myles, Nicholas Veldhuis Nigel Bunnett, Elva Zhao Nigel Bunnett, Daniel Poole
Tissue-specific role of biased signalling at the CaSR
Probing an allosteric binding site in the human calcium sensing receptor
Allosteric pharmacoregulation of a headless calcium sensing receptor
Biased allosteric modulators of metabotropic glutamate receptor 5: a novel therapeutic strategy for CNS disorders
Illuminating inflammatory signalling
Intracellular drug delivery: a route to more selective and effective treatments for disease
Trafficking of G protein-coupled receptors: a new pathway to pain
Mechanosensation in the nervous system: implications for visceral pain
Compartmentalized signalling of opioid receptors
Protease-activated receptors: mediators of the inflammation and pain
A window into pain: protease signalling in pain states
Regulation of PAR2 signaling by RGS proteins
Bile acid signalling in the intestine: a new target for digestive and inflammatory diseases
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
THE EFFECTS OF THE TIMING OF INTRAVENOUS LIPID
EMULSION ADMINISTRATION ON ABSORPTION AND
BIOAVAILABILITY OF ORALLY ADMINISTERED LIPOPHILIC
TOXICANTS IN A RODENT MODEL OF ORAL AMITRIPTYLINE
TOXICITY
Supervisors: Professor Andis Graudins1
Dr Dimitri Gerostamoulos2
Location: Clinical and Experimental Toxicology Laboratory1
Department of Pharmacology
Monash University, Clayton
Victorian Institute for Forensic Medicine (VIFM)2
Kavanagh Street
Southbank, Melbourne
Background:
Intravenous lipid emulsion (ILE) is recommended as an adjunctive therapy in the treatment
of severe cardiovascular drug poisoning after overdose with lipophilic drugs such as the
tricyclic antidepressant amitriptyline. It is postulated to have a number of mechanisms of
action, however, the most accepted is the lipid sink theory. It is postulated that ILE
creates an intravascular lipid sink of drug, preventing its delivery to target organs such as
the heart.
Little is known regarding the effect of timing of ILE administration with respect to timing
of oral toxicant ingestion. A pilot study in our lab suggested that early treatment with ILE
was associated with significantly higher blood amitriptyline concentration and poorer
survival than animals treated with standard antidotes for this poisoning. It is currently
unknown whether this effect is related to enhanced absorption or increased bioavailability
in the presence of ILE treatment.
Project aims: To assess the pharmacokinetics and toxicity of amitriptyline in moderate
overdose following early and late ILE administration in a rodent model. Does early ILE
administration increase drug bioavailability and worsen toxicity?
Techniques: Utilising anaesthetized whole animal model of amitriptyline toxicity with
invasive haemodynamic monitoring. Blood samples to be collected and defined time
intervals. ILE to be administered early at time of oral drug delivery and late after drug
absorption. Drug assays to be performed by the student after training using GC/MS, at
the VIFM, Southbank. Pharmacokinetic assessment of blood drug concentrations.
Assessment of physiological outcomes and survival.
Contact: Prof Andis Graudins: [email protected]
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
EVALUATION & DEVELOPMENT OF WEB-BASED
PHARMACOLOGY RESOURCES
Supervisors: Dr Elizabeth Davis & Dr Eva Patak
Location: Pharmacology Education Research Initative
Department of Pharmacology
Monash University, Clayton
Background:
Our group aims to gain a better understanding of factors that influence the engagement
of students with their learning of pharmacology and the development of resources and
curricula to support students in their learning, particularly within the science and medical
courses.
Project aim:
This group is currently involved in several ongoing projects and prospective students could
become involved in aspects of these. Projects involve the development and evaluation of
web-based learning resources and activities to encourage active learning. In addition, we
want to assess the use of communication tools (including social media) to encourage
interaction and learning.
Techniques:
Techniques used in education-based projects include development of teaching material,
monitoring of use and student evaluation through surveys and focus groups.
Contacts:
Dr Elizabeth Davis Department of Pharmacology
Monash University
Phone: 9905 5755, Rm E123
Dr Eva Patak Department of Pharmacology
Monash University
Phone: 9905 5783, Rm E117
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
INVESTIGATING NOVEL ANTI-FIBROTIC THERAPIES
Supervisors: Dr Chrishan Samuel & Dr Simon Royce
Location: Fibrosis Laboratory (Rms E101/E102)
Department of Pharmacology
Monash University, Clayton
Background:
Fibrosis is defined as the hardening and/or scarring of various organs including the
heart, kidney and lung; which usually arises from abnormal wound healing to tissue injury,
resulting in an excessive deposition of extracellular matrix components, primarily
collagen. The eventual replacement of normal tissue with scar tissue leads to organ
stiffness and ultimately, organ failure. Despite a number of available treatments for
patients with various heart/kidney/lung diseases, patients receiving these therapies still
progress to end-stage organ failure due to the inability of these treatments to directly
target the build-up of fibrosis. Hence, novel and more direct anti-fibrotic therapies are
still required to be established.
Aims:
The Fibrosis Lab aims to identify novel anti-fibrotic therapies (relaxin, stem cells, trefoil
factor 2; and combinations of these) that will more effectively prevent/reverse fibrosis
progression. Additionally, by understanding the mechanisms of action of these potential
therapies of future, we aim to delineate new targets that can be utilized to enhance their
therapeutic potential and abrogation of organ scarring.
Projects:
1. Signal transduction studies (in models of heart / kidney / lung disease)
2. Head-to-head and combination therapy efficacy studies
3. The influence of ageing and gender on fibrosis
4. Development of new approaches to target airway remodeling in asthma
Techniques:
Depending on the project involved, animal/cell culture models of (heart/kidney/lung
disease), blood pressure and functional measurements, matrix biology, protein
biochemistry, molecular biology and/or histological techniques will be utilized.
Contacts:
Dr Chrishan Samuel and Dr Simon Royce Department of Pharmacology
Monash University
Phone: 9902 0152 / 9905 0913
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
CARDIO-PROTECTIVE EFFECTS OF INCRETIN HORMONES:
POTENTIAL BEYOND GLYCAEMIC CONTROL?
Supervisors: Dr Tracey Gaspari & Prof Robert Widdop
Location: Cardiovascular Integrative Group
Department of Pharmacology
Monash University, Clayton
Collaborator: Dr Anthony Dear
Deputy Director, Eastern Clinical Research Unit, Monash University
Background:
Our research focuses on understanding the pathophysiological processes involved in the
development of cardiovascular disease, one of the major causes of illness and death in
Australia and worldwide.
Project aim:
Two classes of diabetic drugs targeting the glucagon-like peptide-1 (GLP-1) pathway are
used clinically to treat Type 2 Diabetes Mellitus. These are GLP-1 receptor agonists
(e.g., Liraglutide) and dipeptidyl peptidase-4 (DPP-4) inhibitors (prolong life of
endogenous GLP-1). In collaboration with Dr Anthony Dear we aim to investigate the
vascular and cardio-protective effect of these classes of drugs in a number of
cardiovascular disease states, including atherosclerosis, vascular injury (neointimal
hyperplasia) and cardiac remodeling.
Techniques:
Projects will incorporate a range of methodologies including: animal dietary and
pharmacological treatments, surgical techniques for vascular injury models,
immunohistochemistry, biochemical measures (western blot, markers of cellular
proliferation and hypertrophy), histological and morphological analyses (such as fibrosis,
intimal to medial measurements).
Contacts:
Dr Tracey Gaspari and Prof Robert Widdop Department of Pharmacology
Monash University
Phone: 9905 4762, Rm E119
Liraglutide
I
M
Vehicle
Figure 1: Representative images of cross-
sectional lesion development in aortic arch of
ApoE KO mice. Liraglutide treatment shows
decreased intima (I) development. Intima (I) and
media (M) areas are identified by dotted line.
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
Untreated brain
Damage
Treated brain
INHIBITION OF ACID SENSING ION CHANNELS (ASIC) AS A
NOVEL TREATMENT FOR STROKE Supervisors: Dr Claudia McCarthy & Prof Robert Widdop.
Location: Integrated Cardiovascular Pharmacology Laboratory
Department of Pharmacology
Monash University, Clayton
Background:
Stroke is the third largest cause of death and the major cause of disability in
industrialised countries. Despite this there is only one approved treatment for patients
with stroke. Severe oxygen depletion during stroke forces the brain to switch from
aerobic to anaerobic respiration, which subsequently results in the production of lactic
acid and a drop in the extracellular pH. Studies have demonstrated a direct correlation
between brain acidosis and the degree of damage following stroke. Recently it has been
discovered that a group of acid sensing ion channels (ASIC), which are activated by
acidosis, play a role in propagating the spread of neuronal damage caused by stroke
induced acidosis. Targeting these ASIC channels to prevent activation may be a new and
effective approach to reduce the severity of brain damage in patients with acute
stroke.
Project aim:
The aim of this project is to explore the therapeutic potential of ASIC blockers as a
novel treatment for stroke. The neuroprotective capacity of three ASIC inhibitors will
be evaluated in a clinically relevant model of stroke. This study will hopefully establish
ASIC as an effective target to prevent the spread of neuronal damage caused by
stroke and identify a new class of drug that may benefit stroke patients.
Techniques:
This study will utilize an integrated perspective and encompasses both in vivo and in vitro techniques. An animal model of stroke will be implemented in conjunction with behavioral tests which provide a symptomatic endpoint. Several physiological
parameters will be monitored throughout the experimental protocol. Specific organs
will be isolated and preserved to measure stroke-induced changes using histology. In
addition, peripheral changes associated with stroke will be evaluated to; firstly
determine whether stroke severity can be accurately measured using these biomarkers;
and secondly to assess whether a drug effect is reflected by these endpoints.
Contacts: Dr Claudia McCarthy and Prof Robert Widdop
Department of Pharmacology
Monash University
Phone: 9905 0095, Rm E119
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
DRUG DISCOVERY PROGRAM FOR AT2 RECEPTOR LIGANDS Supervisors: Dr Emma Jones1, Dr Mark Del Borgo2 &
Prof Robert Widdop1
Location: Integrated Cardiovascular Pharmacology Laboratory
Departments of Pharmacology1 and Biochemistry2
Monash University, Clayton
Background:
The main effector hormone of the renin angiotensin system (RAS) is angiotensin II
which can stimulate both angiotensin AT1 receptors (AT1R) and AT2 receptors (AT2R).
There is evidence to suggest that there is cross talk between AT1R and AT2R at both
functional and signaling levels. For example, AT1R activation is responsible for the
classical effects of Ang II such as vasoconstriction, whereas AT2R activation opposes
this effect by direct AT2R-mediated vasorelaxation or inhibition of AT1R-mediated
signaling. There is currently intense interest focusing on the AT2R cardiovascular
function, although there are few selective AT2R ligands available to delineate such
effects.
We have a drug discovery program replacing natural amino acids in the Ang II molecule
with synthetic amino acid derivatives (e.g. beta-substituted; D- substituted amino
acids). Our preliminary data have identified a series of novel angiotensin peptide
analogues that exhibit AT2R selectivity, evidenced from both in vitro and in vivo
vasodilator activity.
Project aim:
Therefore, the current project will continue this work and will involve biochemical and
in vitro and in vivo cardiovascular experiments identifying lead compounds with AT2R agonist or antagonist activity.
Techniques:
This project will involve animal work including:
Surgical procedures
In vitro studies of vascular reactivity In vivo measurement of blood pressure
Cell culture
Signaling assays
Contacts: Dr Emma Jones & and Prof Robert Widdop
Department of Pharmacology
Monash University
Emma.Jones @monash.edu
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
PREDICTING COMPLICATIONS ASSOCIATED WITH
HAEMORRHAGIC STROKE
Supervisors: Dr Sanjaya Kuruppu1 & Prof Rob Widdop2
Location: Departments of Biochemistry1 & Pharmacology2
Monash University, Clayton.
Background:
Haemorrhagic stroke (or Subarachnoid Haemorrhage) is characterized by the rupture
of a blood vessel on the surface of the brain. It is a medical emergency requiring
prompt neurosurgery, and nearly 50% of patients dont survive. Nearly a third of the
patients who survive develop lifelong debilitating neurological deficits. At present there
are no methods to accurately identify patients who develop these complications. Early
identification will enable appropriate treatment strategies to be implemented, in order
to prevent or reduce the impact of these neurological deficits.
Project: Soluble Angiotensin Converting Enzyme-2 as a marker of Complications
Associated with Subrachnoid Haemorrhage (SAH).
Project aims: Angiotensin Converting Enzyme-1 (ACE-2) is one of the enzymes that play
a key role in the cardiovascular system. Its known functions include the breakdown of
Angiotensin I and II. The enzyme is expressed by endothelial cells lining blood vessels,
as well as in the heart and kidney. Although initially thought to be bound to the plasma
membrane, recent studies have shown the presence of a circulating form of ACE-2 in
human biological fluids. This project aims to examine if levels of ACE-2 in the biological
fluids of patients with SAH, can be used to predict the onset of complications
associated with SAH.
Techniques: The study will involve working with human biological fluids, enzyme assays
and various biochemistry techniques such as electrophoresis and mass spectrometry.
Contacts:
Dr Sanjaya Kuruppu1 and Prof Rob Widdop2
Departments of Biochemistry1 & Pharmacology2
Monash University
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
MECHANISMS OF INFLAMMATION AND IMMUNITY DURING
THE DEVELOPMENT OF HYPERTENSION
Supervisors: Dr Antony Vinh
Location: Cardiovascular Immunology Group
Department of Pharmacology
Monash University, Clayton
Background:
Inflammation and immunity continue to be a topical area of hypertension research. T cells
and the adaptive immune system are known to play a vital role in the development of
hypertension. We have reported that dendritic cells, which are also known as professional
antigen presenting cells (APCs), potentially present hypertension-specific antigens to
induce T c, dendritic cells can also induce tolerance to prevent T cells from attacking self-
antigens in the body. Therefore, harnessing this tolerogenic potential may represent a
novel antigen-specific approach to prevent hypertension.
Project aim:
The aim of this honours project is to investigate the ability of bone marrow-derived
dendritic cells that have been rendered tolerogenic (inhibits T cell activation), to induce
tolerance and inactivate hypertension specific-T cells.
Techniques:
Several techniques will be used in this project including harvesting bone marrow and its
differentiation into dendritic cells, primary cell culture techniques to induce tolerance
(with/without cell lysate antigens), flow cytometry to confirm tolerogenic DCs (tDCs)
have been created and mixed leukocyte reactions to detect whether tDCs will induce
tolerance in T cells isolated from a hypertensive mouse. Based on outcomes and if time
permits, we will perform adoptive transfer of tDCs into hypertensive mice to observe
whether tDCs can be used as a vaccine to prevent hypertension.
Contacts:
Dr Antony Vinh Department of Pharmacology
Monash University
Phone: 9902 4844, Rm E33
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Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
MODULATION OF NEURONAL OXYTOCIN EFFECTS ON
SOCIAL BEHAVIOUR
Supervisors: Dr Richard Loiacono1 & Dr Siew Yeen Chai2
Location: Neuropharmacology Lab & Neurophysiology Team
Departments of Pharmacology1 & Physiology2
Monash University, Clayton
Background:
Metallo-peptidases cleave amino acids from either the N- and C-termini of peptide
hormones to either generate or degrade biologically active peptides. These enzymes play
important roles in the body and alterations in their activities can impact on a diverse
range of physiological processes in both healthy and diseased states. This project is
focussed on one such enzyme known as insulin-regulated aminopeptidase (IRAP) or
oxytocinase. Oxytocin is known as the social hormone, regulating complex social
behaviours including promoting trust, pair-bonding and has been explored as potential
therapy for social behaviour impairments observed with autism spectrum disorders.
Aim:
This project will investigate the behavioural phenotypes in the oxytocinase deficient
mice to determine if regulation of endogenous oxytocin levels will affect social
behaviour.
Techniques: Behavioural testing, cell culture, immunohistochemistry
Contacts:
Dr Richard Loiacono1 & Dr Siew Yeen Chai2
Departments of Pharmacology1 & Physiology2
Monash University
Phone: Richard 9905 4859 Siew Yeen 9905 2515
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
ARE THE ADVERSE EFFECTS OF HORMONE REPLACEMENT
THERAPY ON STROKE OUTCOME MEDIATED BY G PROTEIN-
COUPLED ESTROGEN RECEPTOR SIGNALLING?
Supervisors: Dr Brad Broughton & A/Prof Chris Sobey
Location: Vascular Biology & Immunopharmacology Group
Department of Pharmacology
Monash University, Clayton
Background:
Stroke is a debilitating disease that can cause permanent neurological damage,
complications, and death. At present, there are very few treatment options available
for patients, thus the development of new treatments is vital to reduce the damage
caused by stroke. In recent years, growing evidence has revealed that estrogen is
neuroprotective against stroke, but confusingly hormone replacement therapy (HRT)
worsens stroke outcome in post-menopausal women. Interestingly, recent work from our
lab has found that activation of a novel estrogen receptor (G Protein-coupled Estrogen
Receptor, GPER), which is widely distributed throughout the brain, increases cerebral
infarct damage in males following stroke. Therefore, we hypothesise that GPER
activity affects outcome of HRT therapy in females after stroke.
Project aim:
The aim of this project is to investigate the importance of GPER in mediating the
adverse effects of HRT in stroke. The outcomes of the proposed project are expected to confirm that estrogen therapy has an adverse effect on stroke outcome in young ovariectomised mice due to activation of GPER signalling.
Techniques:
Techniques that will be used during this project include treating mice with estrogen and
various GPER ligands, histochemical approaches to measure cerebral infarct damage,
immunohistochemistry to examine the distribution of GPER in the brain and Western
blotting to determine GPER expression levels.
Contacts:
Dr Brad Broughton & A/Prof Chris Sobey Department of Pharmacology
Monash University
Phone: 9905 0915, Rm EG20
Vehicle Estradiol
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
EXPLORING THE VASOPROTECTIVE ACTIONS OF
NOVEL HNO DONORS
Supervisors: Dr Barbara Kemp-Harper
Location: Vascular Biology & Immunopharmacology Group
Department of Pharmacology
Monash University, Clayton
Background:
Nitric oxide (NO), is an important endogenous vasodilator and regulator of vascular tone.
In disease states such as hypertension and atherosclerosis, the NO signaling pathway is
impaired leading to reduced blood flow to vital organs such as the brain and heart. Whilst
nitrovasodilators can be used to overcome dysfunctional NO signaling, the clinical
application of these agents is limited due to their susceptibility to scavenging by
superoxide and tolerance development.
Importantly, NO can also exist in the reduced state as nitroxyl (HNO) and recent
evidence suggests that this nitrogen oxide is also generated endogenously and has distinct
pharmacological properties and therapeutic advantages over NO. Thus HNO is not
scavenged by superoxide, does not develop tolerance and can target distinct signaling
pathways to cause vasorelaxation. As such, the bioavailability of HNO is preserved in
disease. With a suite of vasoprotective actions, HNO donors have therapeutic potential in
the treatment of cardiovascular disease. Currently, however the clinical utility of these
donors is limited by their short-half lives and byproducts. Excitingly, new pure HNO
donors with longer half-lives are being developed and this study will elucidate the
therapeutic potential of these drugs in the setting of atherosclerosis.
Project aim:
The aim of this honours project is to investigate the ability of novel HNO donors to serve
as vasoprotective agents in the setting of atherosclerosis.
Techniques:
It is anticipated that the project will involve the use of techniques to assess the
vasodilator (small vessel myography), anti-aggregatory and superoxide suppressing
(chemiluminescence) actions of novel HNO donors in control and atherosclerotic mice.
Contacts:
Dr Barbara Kemp-Harper Department of Pharmacology
Monash University
Phone: 9905 4674, Rm E140
HNO VSMC Relaxation Proliferation
.
O2
-
.
O2
-
.
O2
-
Superoxide Production
Platelet Aggregation
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
EXPLORING THE ROLE OF NOX5 IN VASCULAR FUNCTION
Supervisors: Dr Barbara Kemp-Harper & A/Prof Grant Drummond
Location: Vascular Biology & Immunopharmacology Group
Department of Pharmacology
Monash University, Clayton
Background:
Oxidative stress is a major cause of the vascular inflammation, remodeling and
dysfunction associated with hypertension and atherosclerosis. NOX5 is a recently
described reactive oxygen species (ROS)-generating enzyme, which in humans is
expressed in 3 of the major cell types involved in vascular disease (endothelial, vascular
smooth muscle and macrophages). Moreover, NOX5 expression is upregulated in the
vascular wall of coronary artery disease patients. However, the absence of NOX5 from
the rodent genome has hampered efforts to determine whether it directly contributes to
the pathogenesis of vascular disease. In this proposal, we will utilize 'humanized' mouse
models of NOX5 expression to assess NOX5 as a contributor to, and target for therapy
in, vascular injury during hypertension and atherosclerosis.
Project aim:
The aim of this honours project is to investigate the role of endothelial NOX5 in the
modulation of vascular function. This study may lead to the development of more effective
therapies for the treatment of vascular disease.
Techniques:
The project will utilize mice which transgenically express NOX5 in endothelial cells and
will involve the use of assays to detect inflammation (RT-PCR, western blotting,
immunohistochemistry), reactive oxygen species generation (chemiluminescence) and
vascular dysfunction (small vessel myography).
Contacts:
Dr Barbara Kemp-Harper and A/Prof Grant Drummond Department of Pharmacology
Monash University
Phone: 9905 4674, Rm E140
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
INFLAMMATORY MECHANISMS IN ISCHEMIC STROKE
Supervisors: A/Prof Chris Sobey & Dr Helena Kim
Location: Vascular Biology & Immunopharmacology Group
Department of Pharmacology
Monash University, Clayton
Background:
Stroke is the second leading cause of death and is due an interruption of brain blood flow
by a blockage (ischemia) or a rupture (haemorrhage) in an artery. Cerebral ischemia
triggers a cascade of complex events including excitotoxicity, oxidative stress, and up-
regulation of pro-inflammatory molecules and transcription factors that lead to apoptosis.
Inflammatory mechanisms, associated with the infiltration of numerous types of immune
cells, are now a major focus of stroke research because they are suspected to contribute
substantially to secondary brain damage. Nuclear factor kappa B (NF-kB) is a transcription
factor that modulates gene expression of a range of cytokines and other pro-inflammatory
molecules. Recent findings suggest that inhibition of NF-kB, especially those expressed in
neurons, provide neuroprotection following stroke.
Project 1 aim: Investigate the role of endothelial NF-kB on stroke outcome using mice
overexpressing NF-kB inhibitor, IkBk, in vascular endothelium. This study will elucidate
the potential therapeutic effect of blocking NF-kB and/or downstream pathways following
stroke and may lead to the development of more effective stroke therapies.
Project 2 aim: Investigate the importance of specific types of inflammatory responses
e.g. Th1 versus Th2 - in contributing to stroke outcome. This study will identify the types
and numbers of activated immune cells infiltrating the brain following stroke, in order to
block effects of culprit cells and help develop new types of stroke therapies.
Techniques:
These projects will measure behavioural deficits, brain infarct size, immune cell
infiltration and inflammatory markers in mice following stroke.
Contacts:
A/Prof Chris Sobey and Dr Helena Kim Department of Pharmacology
Monash University
Phone: 9905 4189, Rm E148
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
INVESTIGATING THE ROLE OF ALDOSTERONE IN PROMOTING
INFLAMMATION DURING ATHEROSCLEROSIS
Supervisors: Dr Sophocles Chrissobolis & A/Prof Chris Sobey
Location: Vascular Biology & Immunopharmacology Group
Department of Pharmacology
Monash University, Clayton
Background: Atherosclerosis, a chronic disease characterized by chronic inflammation of
the arterial wall, is the underlying pathological process for both coronary and cerebral
artery disease, which are the two most common forms of cardiovascular disease.
Aldosterone, synthesized from cholesterol in the adrenal cortex, acts on the kidney to
promote sodium reabsorption, water retention and potassium excretion, thus modulating
electrolyte and fluid homeostasis and blood pressure. However, elevated aldosterone
levels are an independent cardiovascular risk factor. During atherosclerosis, the role of
aldosterone in promoting inflammation in the vasculature and other organs important in
cardiovascular disease (such as the kidney and brain) is not well characterized.
Project aim:
The aim of this honours project is to investigate the role of aldosterone in promoting
inflammation in the vasculature, brain and the kidneys during atherosclerosis. This may
reveal potential targets to minimize damage in these organs that occurs during
atherosclerosis.
Techniques:
It is anticipated that this project will involve surgeries on mice to administer aldosterone,
and the use of assays to measure blood pressure (tail cuff), atherosclerotic plaque
formation, inflammatory cell markers (RT-PCR), and immune cell numbers (flow cytometry)
in atherosclerotic mice.
Contacts:
Dr Sophocles Chrissobolis and A/Prof Chris Sobey Department of Pharmacology
Monash University
Phone: 9905 0914, Rm E139A
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
INVESTIGATIONS INTO THE ROLES OF NADPH OXIDASES IN
INFLUENZA A VIRUS INDUCED LUNG INJURY
Supervisor: Dr Stavros Selemidis
Location: Oxidant and Inflammation Biology Group,
Department of Pharmacology,
Monash University, Clayton.
Background:
Current drug therapies to treat
influenza pathology are focused
primarily on halting mechanisms of viral
infection and replication. Far less
attention has been directed to
identifying mechanisms of host
defense that lead to the acute lung
injury. Animal and human studies
provide compelling evidence that the acute lung injury following influenza A virus infection
is caused by reactive oxygen species (ROS) production such as superoxide anion.
Importantly, the primary sites of influenza A virus infection, airway epithelial cells, and
resident and infiltrating macrophages are key sites of ROS production via Nox1- and
Nox2-containing NADPH oxidases, respectively. Our preliminary studies have identified
the Nox1 and Nox2 enzymes as novel targets for modulating pathology irrespective of the
infecting influenza strain.
Project aims: The aim of this honours project is to investigate the roles of NADPH
oxidases in influenza A virus induced lung injury and inflammation. To achieve this a
multidisciplinary honours project has been devised. It is anticipated that these studies
will have a major impact on modern drug discovery focusing on oxidative stress caused by
influenza A viruses.
Techniques: This will involve the use of live influenza viruses, cell culture and in vivo
animal models; and assays to detect NADPH oxidase expression and localization (western
blotting, immunohistochemistry, QPCR), ROS generation (chemiluminescence,
immunocytochemistry) and inflammatory cell characterization (flow cytometry).
Contacts: Dr Stavros Selemidis, Rm E137
Department of Pharmacology, Monash University
Phone: 9905 5756,
Website: http://www.med.monash.edu.au/pharmacology/research/oxidant.html
Email: [email protected]
External supervision: A/Prof Ross Vlahos, Department of Pharmacology
The University of Melbourne. Tel: 8344 4221; Email: [email protected]
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
PHARMACOLOGICAL CHARACTERISATION OF VENOMS
Supervisors: Dr Sanjaya Kuruppu1, Dr Oden Kleifeld1,
Professor Wayne Hodgson2
Location: Monash Venom Group
Departments of Biochemistry1 & Pharmacology2
Monash University, Clayton
Background:
Snakebite is a global public health problem. Venoms are composed of many proteins and
detailed knowledge of these components is of importance, for both antivenom
manufacture and identification of new leads for future pharmaceuticals. Our lab uses
cutting edge techniques to purify these proteins and characterize them
pharmacologically using both in vitro and in vivo techniques.
Project 1 : Muscle Damage Induced by African Puff Adder Venom
Supervisors : Dr Sanjaya Kuruppu and Prof Wayne C Hodgson
The African Puff Adder (Bitis arietans) is described as one of the most dangerous snakes in the continent. Life threatening effects of envenoming include haemorrhage,
and damage to muscle tissue which in some cases leads to limb amputation. This project
will use various types of chromatography to purify the toxin(s) responsible for causing
damage to muscle tissue. The purified toxins will be tested in a range of in vitro and in vivo pharmacological assays. The project will also examine the ability of currently available antivenoms to neutralise the effects of these toxins.
Project 2 : Development of Proteomic System-Wide Approach for Characterization
of Snake Venoms
Supervisors: Drs, Oded Kleifeld, Sanjaya Kuruppu and
Prof Wayne C Hodgson.
The routine methods to determine the identity of venom
proteins can be labor intensive, and in many cases provide
only partial sequence information due to technical
limitations and/or lack genomics information. The aim of
this honours project is to develop and test new proteomic
workflow for that will allow full protein sequencing and
characterization of snake venom proteome. Experiments will
involve protein extraction, proteolytic digestion, peptide
separation, liquid chromatography coupled tandem mass
spectrometry (LC-MS/MS) and bioinformatics (MS/MS data
analysis, de novo protein sequencing and more).
Contact:
1) Dr Sanjaya Kuruppu; Email : [email protected]
2) Dr Oded Kleifeld; Email : [email protected]
3) Prof Wayne C Hodgson; Email : [email protected]
Suggested workflow
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
TARGETING THE HUMAN PLATELET THROMBIN RECEPTOR,
PAR4, AS A NOVEL ANTI-THROMBOTIC THERAPY
Supervisor: Dr Justin Hamilton, A/Prof Grant Drummond
Location: Platelet & Megakaryocyte Cell Biology Lab
Australian Centre for Blood Diseases
AMREP (Alfred Hospital Campus), Prahran
Background:
Arterial thrombosis is the most common cause of death and disability in Australia.
Platelets are the blood cells which form arterial thrombi. Therefore our research
examines platelet function in order to discover improved antithrombotic therapies.
Thrombin is the most potent platelet activator and functions via protease-activated
receptors (PARs). We have shown that PAR knockout mice are protected against
thrombosis (see Figure), suggesting PAR antagonists as novel antithrombotic agents. As a
result, PAR antagonists are currently in clinical trial for the prevention of arterial
thrombosis. However, human platelets have two thrombin receptors, PAR1 and PAR4.
Current antagonists target only PAR1, and PAR4 function is poorly understood. To address
this, we have recently developed an antagonist of human PAR4.
Project aim:
This project will utilize our newly developed PAR4 antagonist to determine the
contribution of PAR4 to thrombus formation and stability in human blood. The major
outcome of these studies will be a determination of the importance of PAR4 on human
platelets and of the utility of PAR4 antagonists in preventing arterial thrombosis.
Techniques:
The project will use functional experiments on isolated platelets, ex vivo whole blood
thrombosis experiments, and confocal microscopy, and will appeal to students interested in
researching and developing future therapies for heart attack and stroke.
Contact:
Dr Justin Hamilton
Australian Centre for Blood
Diseases Monash University
Phone: 9903 0125
In vivo thrombosis: Shown are platelets (red) in arterioles of control or PAR4-deficient mice at various times after vascular injury. Note the limited thrombus growth in PAR4-deficient mice. (Vandendries, Hamilton, et al, PNAS, 2007).
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
DEVELOPING ISOFORM-SPECIFIC PI3K INHIBITORS
AS NOVEL ANTI-PLATELET AGENTS
Supervisors: Dr Justin Hamilton, A/Prof Grant Drummond
Location: Platelet & Megakaryocyte Cell Biology Lab
Australian Centre for Blood Diseases
AMREP (Alfred Hospital Campus), Prahran
Background:
Arterial thrombosis is the leading cause of death and disability in industrialized nations.
Anti-platelet agents are the primary preventative therapy for this, but remain limited in
their effectiveness. Identifying improved anti-platelet approaches is the major focus of
our group. We have shown that a family of intracellular signalling enzymes, the
phosphoinositide 3-kinases (PI3Ks), is important for platelet function during thrombosis.
We developed a series of PI3K-deficient mice and showed that these mice have impaired
platelet function, providing proof-of-principle evidence that inhibiting these enzymes may
lead to new anti-platelet drugs. However, there are currently no pharmacological inhibitors
of these PI3K isoforms. This project will develop and test the first isoform-specific PI3K
inhibitors.
Project aim:
To develop the first isoform-specific inhibitors of Class II PI3Ks, and to test lead
compounds in order to determine the suitability of targeting Class II PI3Ks as an anti-
thrombotic approach in humans.
Techniques:
The student will prepare and screen a designed library of compounds for inhibitory
activity against purified PI3K proteins, and will thereby perform protein expression/
isolation techniques and an established in vitro kinase activity screen. Lead compounds
from this initial work will then be tested for anti-platelet activity in functional assays
routinely used in our lab (see Figure). This project will appeal to students interested in
drug design & development and in testing potential heart attack and stroke therapies.
Contact:
Dr Justin Hamilton
Australian Centre for Blood Diseases Monash University
Phone: 9903 0125
Examining thrombosis: A 3D
reconstruction of a platelet thrombus made using confocal microscopy
A platelet at work: F-actin of the cells cytoskeleton stained
with TRITC-phalloidin.
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
STRATEGIES TO RESCUE DIABETES-INDUCED HEART FAILURE
Supervisors: A/Prof Rebecca Ritchie & Dr Barbara Kemp-Harper
Location: Heart Failure Pharmacology, Baker IDI Heart &
Diabetes Institute, 75 Commercial Rd, Prahran
Background:
Our laboratorys research focuses on identifying intra-cardiac regulators of growth and
function, to better prevent and treat the causes of heart failure. Diabetes impairs cardiac
muscle function and relaxation, increasing the risk of death from heart failure by more
than 2-fold. We have demonstrated the causal role of excess generation of reactive
oxygen species (ROS) in diabetes-induced heart failure, in both type 1 and type 2 diabetes
(Huynh et al Diabetologia 2012,55:1544-53; Huynh et al Free Rad Biol Med 2013,60:307-17). Cardiac-selective activation of physiological growth signalling prevents both diabetes-
induced upregulation of cardiac reactive oxygen species, and diabetes-induced heart
failure (Ritchie et al Diabetologia 2012,55:3369-81). We are now exploring mechanisms downstream of ROS and physiological growth signalling, in order to better understand, and
develop new treatments for, diabetes-induced heart failure.
Project aim:
The aim of this project is to investigate a novel potential therapeutic strategy for
rescuing cardiac function and structure in the diabetic heart. It will determine whether
post-translational protein modifications induced by high glucose play a causal role in
development of diabetes-induced heart failure. Whether treatments that limit these
protein modifications prevent diabetes-induced cardiac dysfunction (and the impact on
cardiac structure and morphology) will also be investigated. This work may lead to
development of more effective therapies for restoring cardiac function in diabetes.
Techniques:
This project uses rodent models of chronic diabetic cardiac disease. Changes in cardiac
function (either in the isolated heart ex vivo or in the intact heart in vivo), blood pressure and cardiac structure/morphology (fibrosis, hypertrophy, inflammation, apoptosis, ROS
generation) will be measured. Assays include Westerns, chemiluminescence, ELISA, real-
time PCR, histology and/or immunohistochemistry.
Contact:
A/Prof Rebecca Ritchie, Baker IDI Phone: 8532 1392
cardiomyocyte
NADPH oxidase
Nox2
p47
p2
2
DIABETES
glucose
+
O2-
O2-
+
mitochondria
mitochondrial uncoup-ling & dysfunction
apoptosis
NO
ONOO- 3NT
Inflammation
hypertrophy
cardiac fibrosis
ACE
Ang IIAng I +
O2-
LV diastolic function
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
NITROXYL PROTECTS AGAINST THE CAUSES OF HEART
FAILURE
Supervisors: A/Prof Rebecca Ritchie & Dr Barbara Kemp-Harper
Location: Heart Failure Pharmacology, Baker IDI Heart &
Diabetes Institute, 75 Commercial Rd, Prahran
Background:
Our laboratory has identified the NO/cGMP signalling system as a powerful cardiac
antihypertrophic mechanism (Ritchie et al Pharmacol Ther 2009;124:279-300). Nitroxyl (HNO), a novel redox sibling of NO, has therapeutic advantages for treatment of
cardiovascular diseases. We have shown that HNO prevents hypertrophy (abnormal
pathological growth) and generation of reactive oxygen species (ROS) in isolated
cardiomyocytes (Lin et al PLOS One 2012;7(4):e34892; Irvine et al Am J Physiol 2013;305:H365-77). HNO (but not NO) also potentiates cardiac function, via direct
interactions with cardiac calcium handling proteins (e.g. SERCA2a, RyR2). Activity and
expression of these proteins is imapired in cardiac pathologies (cardiac hypertrophy,
heart failure, diabetes). Together with ROS upregulation, these changes contribute to
development of cardiac dysfunction. HNO is thus likely favourable for treating cardiac
pathologies; we are now exploring the potential mechanisms by which acute and chronic
HNO therapy protects cardiac function in hypertension, hypertrophy and/or diabetes.
Project aim:
The aims of this project are to investigate (i) whether the mechanisms by which HNO
acutely enhances cardiac function in the intact heart are different to those that prevent
hypertrophy and suppress ROS; and (ii) determine if acute or chronic HNO treatment is
cardioprotective in isolated cardiomyocytes and/or the intact myocardium in vivo in settings of chronic cardiac impairment. The outcome of this project will be definitive
information regarding the mechanism(s) and effectiveness of HNO-mediated rescue of
myocardial dysfunction.
Techniques:
This project uses rodent models of cardiac disease, which may include cultured cells
(cardiomyocytes and/or cardiac fibroblasts), isolated hearts ex vivo or intact hearts in vivo. Changes in cardiac function, blood pressure and cardiac morphology (hypertrophy, fibrosis, ROS) will be measured, using Westerns, chemiluminescence, ELISA, real-time
PCR, histology and/or immunohistochemistry analyses.
Contact:
A/Prof Rebecca Ritchie, Baker IDI Phone: 8532 1392
heart failure
cGMP thiol reactivity
SERCA/RyRfunction
XX X
cardiac function
SERCA/RyRfunction
cardiac hypertrophy cardiac fibrosis
ROS
Heart disease (e.g. Hypertension, Diabetes)
Nitroxyl
X
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
ANNEXIN-A1 PROTECTS AGAINST CARDIAC INFLAMMATION
Supervisors: A/Prof Rebecca Ritchie & Dr Barbara Kemp-Harper
Location: Heart Failure Pharmacology, Baker IDI Heart &
Diabetes Institute, 75 Commercial Rd, Prahran
Background:
Myocardial ischaemic injury (such as heart attack) induces an inflammatory response,
resulting from both infiltration of circulating inflammatory cells, as well as direct actions
on myocardium and endothelium (via Ca2+ overload, reactive oxygen species (ROS)
upregulation or mitochondrial dysfunction). In addition to increased cardiac cell death,
recovery of cardiac function is impaired. We have shown that the diabetic heart also
exhibits an inflammatory phenotype (Huynh et al Free Rad Biol Med 2013,60:307-17). Both disorders increase risk of heart failure. The endogenous anti-inflammatory protein
annexin-A1 (ANX-A1) protects against cardiac injury and loss of cardiac function (Ritchie
et al Eur J Pharmacol 2013;461:171-9; Ritchie et al Br J Pharmacol 2005;145:495-502; Qin et al Br J Pharmacol 2013;168:23852), at least in the short-term. We are now exploring the potential for, and the mechanisms responsible, ANX-A1 to protect against cardiac
inflammation and resultant heart failure over the longer-term, in both myocardial
infarction (MI, heart attack) and diabetes.
Project aim:
The project will test the hypothesis that ANX-A1 represents a novel modulator of
inflammation, viability and function of the heart following MI and diabetes. It will also
investigate the receptors responsible (e.g. FPR1 or FPR2) for cardioprotection, and
examine potential therapeutic opportunities offered by synthetic ANX-A1 mimetics. This
work may lead to development of effective therapies for treating cardiac inflammation
resulting from diabetes and/or MI, to reduce progression to heart failure.
Techniques:
This project uses rodent models of chronic cardiac disease. Changes in cardiac function (in
isolated heart ex vivo or intact heart in vivo) & morphology (inflammation, apoptosis, necrosis, fibrosis) will be measured, via Westerns, real-time PCR, histology,
immunohistochemistry and other assays. Cardiac myocytes
or fibroblasts may also be used.
Contact:
A/Prof Rebecca Ritchie, Baker IDI Phone: 8532 1392
HONOURS PROJECT 2014
ANX-A1 mimetics
early rescue of contractile function
preservation of cardiac morphology
preservation of contractile function
inflammation in vivo
myocardial viability
FPR1
heart failuredeath
XX
FPR2
GGq/11 GP-Akt
Gi/o
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
THE ROLE OF HNO IN MACROPHAGE POLARIZATION
Supervisors: Dr Jennifer Irvine, Dr Karen Andrews &
Dr Barb Kemp-Harper
Location: Vascular Pharmacology Baker IDI Heart & Diabetes Institute
Prahran
Background:
Vascular inflammation is a critical early event in the development of atherosclerosis,
involving the recruitment and adhesion of monocytes to the endothelium. The monocytes
then transmigrate through the vessel wall into tissue, where they differentiate into
macrophages. Under physiological conditions, the monocyte-derived macrophage is of the
M2 type playing a normal protective role in the organism. When pathological factors
(including inflammation) are present, the differentiated macrophage possesses features
which damage tissue, and this type of macrophage is normally termed M1. M1 macrophages
play an important role in cardiovascular disease. For example, M1 macrophages turn into
foam cells through the uptake of ox-LDL in atherosclerosis, forming pathological lipid
lesions on the vessel wall. The vasoactive properties of nitric oxide (NO) are well
recognized, yet it is becoming increasingly apparent that nitroxyl (HNO), a redox sibling
of NO, exhibits distinct pharmacology from NO and may itself play a significant
vasoprotective role.
Project aim:
This project aims to explore the potential effects of HNO on macrophage polarization.
We will isolate monocytes from human blood, differentiate them into macrophages, and
induce the macrophages into M1 or M2 states respectively. We will then study the
influence of treatment with HNO donors on the induction of M1 or M2 macrophages.
Techniques:
It is anticipated that this project will involve the use of cell culture techniques, flow
cytometry (surface marker expression), quantitative PCR (gene expression), cell
morphology and reactive oxygen species generation (chemiluminescence).
Contacts:
Dr Jennifer Irvine and Dr Karen Andrews
Vascular Pharmacology Baker IDI Heart & Diabetes Institute
Phone: 8532 1238
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
CENTRAL MECHANISMS IN THE CONTROL OF BLOOD PRESSURE
Supervisors: Professor Geoffrey A. Head
Location: Neuropharmacology Laboratory
BakerIDI Heart & Diabetes Institute
Prahran
Background:
Our laboratory explores the role of the sympathetic nervous system in the development
and maintenance of hypertension with a particular emphasis on the central pathways and
neurotransmitters which contribute to the long term adaptive changes which lead to
hypertension in obesity and during chronic stress.
Research Projects: For further information on research projects on offer please contact
Professor Geoff Head.
Contact:
Prof. Geoffrey Head Baker IDI Heart & Diabetes Institute
Phone: 03 8532 1332
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
TARGETING NADPH OXIDASE USING PHARMACOLOGICAL
INHIBITORS FOR TREATMENT OF OCULAR
NEOVASCULARISATION
Supervisors: Dr Hitesh Peshavariya1 & A/Prof Grant Drummond2
Location: Cytoprotection Pharmacology Group
Centre For Eye Research Australia1
Department of Pharmacology, Monash University2
Background:
Ocular neovascularisation (of the retina and choroid) underlies the pathogenesis of severe
vision loss and is a growing public health problem in Australia and worldwide, making major
contribution to diabetic retinopathy and macular degeneration, respectively.
Neovascularisation is involved in the repair of tissues such as the retina after ischemic
insult. This is an indispensable process for tissue repair which involves proliferation,
migration and capillary formation by endothelial cells. Redox signalling mediated by
NADPH oxidase has been implicated in neovascularisation in vivo of the retina and choroid.
We have discovered pharmacological candidates that specifically modulate the expression
of Nox4 type NADPH oxidase in endothelial cells and in vivo. Inhibition of Nox4 type
NADPH oxidase could create new opportunities for treatment of patients with diabetic
retinopathy and other proliferative retinopathies including wet age-related macular
degeneration
Project aim:
In this project first we will investigate the role of NADPH oxidase isoforms (Nox1, Nox2
and Nox4) in both oxygen-induced retinal neovascularisation or laser-induced choroidal
neovascularisation in mice. Second, we will investigate pharmacological intervention with
Nox4 inhibitors using in vitro and in vivo models of ocular neovascularisation, and
determine whether the same effects are seen in Nox4-deficient mice.
Techniques:
These studies will use pharmacological, molecular and cell culture tools as well as knockout
mice, and mouse models of ocular neovascularisation.
Contacts: Dr. Hitesh Peshavariya Ph.D
Centre for Eye Research Australia
University of Melbourne
Level 1, 32 Gisborne Street
EAST MELBOURNE VIC 3002
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
THE USE OF DRIED BLOOD SPOTS (DBS) IN FORENSIC
TOXICOLOGY
Supervisors: Dr Dimitri Gerostamoulos1,2 & Dr Jennifer Pilgrim1,
Location: 1 Department of Forensic Medicine, Monash University, 2 Victorian Institute of Forensic Medicine, Southbank, Victoria.
Background: The application of routine toxicology to coroners/medical examiner/police
cases is all but essential in medico-legal investigations. In order to determine whether
drugs and/or poisons may have contributed to an accident, assault or death, or whether
a person may have been under the influence of drugs at the time of an event, blood,
among other tissue samples, can provide valuable information.
Samples of blood collected from victims of crime, drug impaired drivers and deceased
persons undergo a routine toxicological analysis typically involving immunoassays and
other chromatographic/mass spectrometric techniques (GC/MS or LC/MS). The
specimen of blood can vary in volume from 0.1 1mL depending on the type of analysis.
Often multiple tests are conducted on one sample and so there is need for up to 5-10
mL to be collected for toxicological purposes. Dried blood spots (finger prick resulting
in a small volume of blood applied to a blotting card) may seek to provide an alternative
to traditional blood sampling.
The use of dried blood spots (DBS) is not new in toxicology but has recently been
examined more closely for its usefulness in forensic cases, especially in instances where
low volumes of blood are collected or only small amounts of blood have been collected as
evidence (Stove et al., 2012). Applications of DBS now included therapeutic drug
monitoring, environmental contaminants and trace elements. Recently DBS have been
used to detect novel psychoactive substances in forensic casework (Ambach et al.,
2013, Jantos et al., 2011).
Project aim: This honours project focuses on developing an extraction technique in DBS
for the isolation and identification of routine drugs for both living and deceased persons.
The developed method will be compared to traditional extraction techniques currently
used in the toxicology laboratory at VIFM. The investigations may lead to novel
applications for screening for drugs in victims of crime and deceased persons. The use
of DBS may be preferential in small children and neonates where the identification of
drugs is satisfactory for case investigations.
References
AMBACH, L., et al., 2013. Rapid and simple LC-MS/MS screening of 64 novel
psychoactive substances using dried blood spots. Drug Test Anal. JANTOS, R., et al., 2011. Analysis of 3,4-methylenedioxymetamphetamine: whole blood
versus dried blood spots. J Anal Toxicol, 35, 269-73. STOVE, C. P., et al., 2012. Dried blood spots in toxicology: from the cradle to the
grave? Crit Rev Toxicol, 42, 230-43. Contacts:
Dr Jennifer Pilgrim [email protected]
Department of Forensic Medicine, Monash Univ [email protected]
Phone: 9252 1582
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
TISSUE-SPECIFIC ROLE OF BIASED SIGNALLING AT THE CaSR
Supervisors: Dr Katie Leach
Location: Drug Discovery Biology
Monash Institute of pharmaceutical sciences, Parkville
Background:
The human calcium sensing receptor (CaSR) primarily acts to sense and regulate
extracellular calcium (Ca2+o) concentrations in the body, but it has a number of non-
canonical roles including control of neuronal and colon epithelial differentiation and
proliferation, nutrient sensing, hormone secretion from intestinal and thyroid cells and
regulation of cardiovascular events. Its diverse functions are related to its widespread
tissue distribution and its ability to bind multiple endogenous ligands. In addition, a
number of small molecule drugs bind the CaSR, one of which, cinacalcet, is used clinically
to treat certain instances of hyperparathyroidism. CaSR ligands exert diverse effects on
receptor signalling, in part due to their ability to stabilise discrete protein conformations,
with each conformation being able to activate its own signature of signalling and
regulatory pathways, termed biased signalling. Biased signalling at the CaSR may have
important implications for therapeutic strategies involving this receptor.
Project aim:
To evaluate biased signalling at the CaSR by a range of endogenous orthosteric agonists
(Ca2+o, Mg2+o, Sr2+o, Fe2+o, Gd3+o), endogenous allosteric ligands (L-phenylalanine,
spermine and -glutathione) and small molecule allosteric modulators (cinacalcet, calindol,
NPS2143, calhex) in distinct cellular backgrounds that represent the diverse tissue
distribution of the receptor, including human embryonic kidney, colon epithelial, neuronal-
like and thyroid derived cell lines. This information will be used to elucidate the distinct
signalling pathways that are important for the (patho)physiological processes mediated by
the CaSR and may lead to the development of more effective therapies for the treatment
of disorders such as neurodegeneration, colon and thyroid cancers and disorders of
calcium homeostasis.
Techniques:
Tissue culture and high throughput signalling assays including ERK1/2 phosphorylation and
intracellular calcium mobilisation to measure receptor signalling events, and fluorescence
activated cytometry to detect cell surface receptor expression levels. The project will fit
data obtained from signalling assays to pharmacological models to quantify parameters
such as ligand binding affinity, allosteric cooperativity and biased agonism.
Contacts:
Dr Katie Leach Drug Discovery Biology
Monash Institute of Pharmaceutical
Sciences Parkville
Phone: 9903 9089
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-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
PROBING AN ALLOSTERIC BINDING SITE IN THE HUMAN
CALCIUM SENSING RECEPTOR
Supervisors: Dr Katie Leach
Location: Drug Discovery Biology
Monash Institute of pharmaceutical sciences
Monash University, Parkville
Background:
The human calcium sensing receptor (CaSR) is a family C G protein coupled receptor
(GPCR) that plays a pivotal role in extracellular calcium (Ca2+o) homeostasis and parathyroid
hormone (PTH) secretion. However, over 200 clinically relevant polymorphisms have been
identified in the CaSR and unfortunately they can result in a number of disorders, such as
autosomal dominant hypocalcaemia (ADH), Bartter syndrome type V, familial hypocalciuric
hypercalcaemia (FHH), familial benign hypercalcaemia (FBH) and neonatal severe
hyperparathyroidism (NSHPT). Cinacalcet, a positive allosteric CaSR modulator prescribed
for the treatment of primary and secondary hyperparathyroidism, was recently shown to
successfully normalise serum Ca2+o in individuals with loss-of-function CaSR mutations,
suggesting that cinacalcet and other allosteric CaSR modulators could be invaluable in the
treatment of disorders linked to CaSR mutations. However, recent molecular modelling and
mutagenesis studies have predicted that the binding site(s) for allosteric CaSR
modulators comprises residues located in the transmembrane (TM) domains and
extracellular loops of the receptor, where a growing number of naturally occurring
mutations are being identified. Thus, it is imperative that we understand how drugs bind
to the CaSR.
Project aim:
To probe the location of an allosteric binding site on the CaSR using mutagenesis of amino
acid residues. This information will lead to a better understanding of how drugs interact
with the CaSR.
Techniques:
Alanine substitution of amino acids will be used to determine the involvement of amino
acids in the function of allosteric modulators. Culture of human embryonic kidney
(HEK293) cell lines expressing the wild type and mutant CaSRs wil be required to evaluate
receptor function using high throughput assays that measure intracellular Ca2+o
mobilization to determine receptor signalling events, and fluorescence activated
cytometry to detect cell surface receptor expression levels. The project will fit data
obtained from signalling assays to pharmacological models to quantify parameters such as
ligand binding affinity and allosteric cooperativity.
Contacts:
Dr Katie Leach Drug Discovery Biology
Monash Institute of Pharmaceutical Sciences, Parkville
Phone: 9903 9089
-
Department of Pharmacology, Honours 2014
Copyright Monash University 2012. All rights reserved. Except as provided in the Copyright Act 1968, this work may not be reproduced in any form without the written permission of the host Faculty and School/Department.
ALLOSTERIC PHARMACOREGULATION OF A HEADLESS
CALCIUM SENSING RECEPTOR
Supervisors: Dr Katie Leach
Location: Drug Discovery Biology
Monash Institute of pharmaceutical sciences, Parkville
Background:
The human calcium sensing receptor (CaSR) is a family C G protein coupled receptor
(GPCR) that plays a pivotal role in extracellular calcium (Ca2+o) homeostasis and
parathyroid hormone (PTH) secretion. It is expressed on the surface of a variety of cell
types throughout the body, where it responds to small increases in free Ca2+o
concentrations. Although the primary Ca2+ (orthosteric) binding site has been localised to
the large extracellular N-terminal region of the receptor, otherwise known as the venus
flytrap (VFT) domain, evidence has pointed towards an additional binding site within the
transmembrane spanning regions of the receptor. This second site is topographically
distinct from the region that binds allosteric calcilytics and calcimimetics, which modulate
the activity of Ca2+o at the CaSR, although it is unclear which amino acids form this
second binding site for Ca2+o.
Project aim:
To investigate the activity of orthosteric and allosteric ligands at a headless CaSR that
lacks the first 599 amino acids that comprise the VFT domain and is thus composed of the
TM domains and a functional but truncated C-terminal tail, which lacks the last 176 amino
acids of the receptor. The extent to which allosteric modulators retain their ability to
regulate CaSR activity in the absence of the primary Ca2+o binding site will be
investigated to gain an understanding of the mechanism of allosteric modulation at the
human CaSR. This information will lead to a better understanding of agonist and allosteric
modulator activity at the CaSR.
Techniques:
Growth and culturing of human kidney embryonic (HEK293) cell lines expressing the wild
type and headless CaSR to evaluate receptor function using high throughput assays that
measure extracellular signal regulated kinases (ERK1/2), intracellular Ca2+o mobilization
to measure receptor signalling events, and fluorescence activated cytometry to detect cell
surface receptor expression levels. The project will fit data obtained from signalling
assays to pharmacological models to quantify parameters such as ligand binding affinity
and allosteric cooperativity.
Contacts:
Dr Katie Leach Drug Discovery Biology
Monash Institute of Pharmaceutical Sciences,
Parkville
Phone: 9903 9089
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