Wilberforce Clark's misunderstanding in the translations ...
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Essay marking scheme0: No answer2 : Fail. Very incomplete or very inaccurate answer, or answer indicating substantial and potentially dangerous misunderstanding.3: Borderline Fail. Poor attempt, inadequate in some respects (for example, with inaccuracies, omissions or irrelevant information)4: Borderline Pass: information is relevant and largely accurate, but indicating little more than a reasonable understanding of the Core5: Pass: answers with good (and relevant) content extending significantly beyond the Core
Answers scoring 5 can be given up to three bonus marks :1 mark: for a well-organised, clear and direct answer to the question, 1 or 2 marks: for the following as they may be possible according to the question set:the appropriate use of experimental evidence, reference to relevant clinical matters, an integrative (as opposed to a narrow) approach, a perceptive/original and relevant discussion.
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The CF Transmembrane Conductance Regulator protein and cystic fibrosis
Syllabus:1.6.5 Transporter structure and function
8.2.4 Tissues of respiratory system
9.5.3 GI secretion
9.5.5 Intestinal electrolyte transport
14.7.4 Secretin control via cAMP of Cl-/HCO3- exchange
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Genetics of cystic fibrosis
Cystic fibrosis (CF) commonest monogenic disease1 in 2500 Caucasian births
1 in 15 carriers7000 people in UK
Autosomal recessive diseaseMost common (~70%) phe506del (F508)>1600 other mutations
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The sweat gland and CF
Quinton 2007 Physiology
“a child that taste salty when kissed will soon die”Alonso y de los Ruyzes 1606
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The sweat gland and CF
Quinton 2007 Physiology
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CF is primarily a lung disease…
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…but not exclusively
• Pancreas– Exocrine– Endocrine (CF related diabetes)
• GI tract – Constipation due to thickened faeces– Malabsorption of vitamin D osteoporosis
• Liver (cirrhosis)– Thickened bile
• Infertility in males – vas deferens absent
See Davies et al (15th Dec, 2007) BMJ for more extensive symptom list
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Lung disease in CF
Life expectancy
<40 yrs
Dav
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et a
l 20
07 B
MJ
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Diagnosis of CF
All babies are given Guthrie blood spot test• measures ↑ immunoreactive trypsinogen• if positive genetic screening & sweat testing
Advantages of early diagnosis: nutritional benefits, early access to care, relatively quick diagnosis, appropriate counselling
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The CF Transmembrane Conductance Regulator protein
CFTR 1480 amino acidsMember of ABC family
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The CFTR protein
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CFTR – how does it work?
Not a classical ABC transportercAMP regulated Cl channelRole of ATP?
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Mutations in CF
Mutations in CFTR can result in trafficking and/or function defects Class IV
Defectiveconduction
Class IIIDefectiveregulation
Class IIDefectiveprocessing
Class IDefective protein production
Class VReduced mRNA and/or protein often due to splicing defects
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F508 is the most common CF mutation
F508 is primarily a class II mutationAccounts for ~70% of CFProtein retained in ER and then degraded by proteosome
F508 is in NBD1, and its mutation makes the domain less temperature sensitive• can increase surface expression by reducing temperature (Denning et al 1992)• ‘correctors’
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Nature, 1992
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What was the rationale for looking at the effects of temperature?
What is the potential clinical significance of the study?
What cells were used?
What are the key results from figure 1, 2 and 4?
Questions
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‘Correctors’ increase surface expression
Chemical chaperones: e.g. glycerol, taurine, can suppress protein-folding defectsDisadvantages: need high (mM) concs as non-
specific effect
‘Correctors’ act as chaperones to rescue cell surface expression
More specific correctors have been found by screening of small molecule libraries (pharmacochaperones)
Work by enhancing folding, decreasing degradation, increasing plasma membrane stability
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‘Correctors’
2. Targeting endogenous molecular chaperones
Could try to either - Pharmacologically decrease interaction with
chaperones that signal degradation- Knock down chaperones with antisense RNA
Mixed/controversial results…
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F508 is also a class III mutant
Even when at the membrane, the conductance of F508 is lower than WT
Need potentiator (drug which increases conductance)- act directly on CFTR- open basolateral K+ channels- open an alternative route for apical Cl- exit
Pharmacology currently seen as more feasable route that gene therapy…
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Difficult to target specific cells, cell turnover relatively high needing continual treatmentUK Cystic fibrosis Gene Therapy consortium performing clinical trials
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Reading primary literature• Introduction
– What was known and not known
– Why did they do the experiment
– What is the fundamental question addressed by the experiment
• Methods Techniques– Overview of techniques; what did they use?
– What are their limitations?
• Results– Each figure is a mini-paper: state why they did it, what was the
technique, what the results show, what do the results mean
• Discussion– Overall merit of paper; clinical significance of findings
– What remains to be done?