Oxidative Stress and Inflammation in Chronic Oxidative Stress and Inflammation in Chronic Kidney Disease: The Nature, Mechanisms, Kidney Disease: The Nature, Mechanisms,

Consequences and TreatmentConsequences and Treatment

N. D. Vaziri M.D., MACPN. D. Vaziri M.D., MACP

Division of Nephrology and Hypertension Division of Nephrology and Hypertension University of California Irvine, Irvine University of California Irvine, Irvine

Part 1- Oxidative Part 1- Oxidative Stress in CKDStress in CKD

- - Oxidative stress is a constant feature of CKD Oxidative stress is a constant feature of CKD

- It is both a cause and a consequence of - It is both a cause and a consequence of inflammationinflammation

- - Together oxidative stress & inflammation Together oxidative stress & inflammation contribute to development & progression of contribute to development & progression of CKD and the associated complications CKD and the associated complications including atherosclerosis, CVD, EPO-resistant including atherosclerosis, CVD, EPO-resistant anemia, immune deficiency, cachexia, among anemia, immune deficiency, cachexia, among othersothers

GPXGPX

Production and Metabolism of Reactive Production and Metabolism of Reactive Oxygen Species (ROS)Oxygen Species (ROS)

•Mitochondria

• Endoplasmic reticulum

•Cyclooxygenase

•Lipooxygenase

•Uncoupled NOS

•NAD(P)H Oxidase

•Xanthine Oxidase

•Cytochrome P-450

OO22 OO22

. SODSOD HH22OO22 OOHH.

HH22O + OO + O22

FeFe2+2+

OO22.

HH22O + GSSGO + GSSG

HOClHOCl

Cl, M

PO

Cl, M

PO

CATCAT

ee--

O22+ 4e (H) 2H2O

+NO

ONOO.OH

Oxidative StressOxidative Stress

Oxidative Stress is a condition in which Oxidative Stress is a condition in which production of reactive oxidative species (ROS) production of reactive oxidative species (ROS) exceeds the capacity of the antioxidant systemexceeds the capacity of the antioxidant system

Biochemical Consequences of Oxidative StressBiochemical Consequences of Oxidative Stress

In presence of oxidative stress, the uncontained ROS In presence of oxidative stress, the uncontained ROS cause tissue damage/dysfunction by:cause tissue damage/dysfunction by:

– Directly attacking , denaturing &modifying structural and functional molecules (e.g. lipids, proteins, carbohydrates, DNA, RNA, NO, etc.)

– Modulating activities of the redox-sensitive transcription factors (e.g. NFκB, AP-1) and signal transduction pathways (Activation of protein kinases e.g. ERK, P53 & ASK1, Ca ATPase release channels), thereby promoting inflammation, ER stress, fibrosis, apoptosis etc.

Mechanisms of Oxidative Stress in CKDMechanisms of Oxidative Stress in CKD

• A- Increased production of reactive oxygen A- Increased production of reactive oxygen species (ROS)species (ROS)

• B- Impaired antioxidant defense systemB- Impaired antioxidant defense system

Factors Contributing to increased ROS Production & Factors Contributing to increased ROS Production & dissemination of oxidative stressdissemination of oxidative stress

• Activation of tissue angiotensin systemActivation of tissue angiotensin system• HypertensionHypertension• InflammationInflammation• Uremic toxins (endogenous; exogenous)Uremic toxins (endogenous; exogenous)• Mitochondrial dysfunctionMitochondrial dysfunction• Accumulation of oxidation-prone lipoprotein remnantsAccumulation of oxidation-prone lipoprotein remnants• Underlying conditions (Underlying conditions (e.g. diabetes, autoimmune diseasese.g. diabetes, autoimmune diseases))• Increased tissue iron loadIncreased tissue iron load ( (Fe shift, blood transfusion, excess IV Fe useFe shift, blood transfusion, excess IV Fe use)) • Iatrogenic causes (Iatrogenic causes (blood/dialyzer interaction, dialysate impurities, blood/dialyzer interaction, dialysate impurities, excessive excessive

use of IV Feuse of IV Fe, rejected transplant kidney, reaction to failed AV grafts, rejected transplant kidney, reaction to failed AV grafts))

A- Sources/mechanisms of excess ROS production in A- Sources/mechanisms of excess ROS production in CKDCKD

• Up-regulation/activation of ROS-producing enzymes (Up-regulation/activation of ROS-producing enzymes (e.g.e.g. NAD(P)H oxidase, cyclooxygenase, lipoxygenase, etcNAD(P)H oxidase, cyclooxygenase, lipoxygenase, etc))

• Uncoupling of NO synthase Uncoupling of NO synthase (via (via monomerization of eNOS, depletion of monomerization of eNOS, depletion of

tetrahydrobiopterin [BH4], accumulation of ADMA )tetrahydrobiopterin [BH4], accumulation of ADMA )

• Impairment of mitochondrial electron transport chainImpairment of mitochondrial electron transport chain

• Activation of leukocytes and resident cellsActivation of leukocytes and resident cells

• Dissemination of oxidative stress by circulating oxidized Dissemination of oxidative stress by circulating oxidized LDL & phospholipids via oxidation chain reaction LDL & phospholipids via oxidation chain reaction

NAD(P)H Oxidase

The major source of ROS production in endothelial cells (NOX-II or gp91 phox ), VSMC (NOX-I and NOX-IV) and renal parenchymal cells (NOX-IV or Renox).

* NAD(P)H oxidase activation involves assembly of enzyme’s membrane-associated subunits (NOXs and p22) with cytosolic subunits (p47, p67 and rac-1).

-

Subunits of NADPH oxidaseNAD(P)H oxidase activation involves assembly of enzyme’s membrane-associated subunits (NOXs and p22) with cytosolic subunits (p47, p67 and rac-1).

NAD(P)H oxidase is the major source of superoxide (O2-)

in the kidney & vessel wall

NOX-1: vascular smooth muscle cells

NOX-3: colon

NOX-4: renal cortex

Up-regulation of NAD(P)H oxidase in the remnant kidney

Cox-2

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12/15 Lipooxygenase

Up-regulation of Cyclooxygenase & lipoxygenase in remnant kidney

Increased ROS production by circulating Increased ROS production by circulating granulocyte in ESRD patients granulocyte in ESRD patients

Mechanisms of Oxidative Stress in CKDMechanisms of Oxidative Stress in CKD

• A- Increased production of reactive oxygen A- Increased production of reactive oxygen species (ROS)species (ROS)

• B- Impaired antioxidant defense systemB- Impaired antioxidant defense system

B- Factors contributing to Antioxidant B- Factors contributing to Antioxidant DepletionDepletion

• Reduced Production of endogenous antioxidants Reduced Production of endogenous antioxidants (antioxidant enzymes, GSH, ApoA1, Albumin, LCAT, Melatonin, etc(antioxidant enzymes, GSH, ApoA1, Albumin, LCAT, Melatonin, etc))

• Impaired activation of Nrf2 Impaired activation of Nrf2 ((the master-regulator of genes the master-regulator of genes

encoding antioxidant/detoxification moleculesencoding antioxidant/detoxification molecules))• Depletion of antioxidant molecules by ROSDepletion of antioxidant molecules by ROS• Diminished antioxidant activity of HDLDiminished antioxidant activity of HDL• Reduced intake of fresh fruits and vegetablesReduced intake of fresh fruits and vegetables ( (K restrictionK restriction))

• Removal of water-soluble antioxidants by dialysisRemoval of water-soluble antioxidants by dialysis• Anemia: (↓Anemia: (↓RBC antioxidants: GSH, GPX, PAF-AH, PhospholipidsRBC antioxidants: GSH, GPX, PAF-AH, Phospholipids))

Adaptive response to oxidative stressAdaptive response to oxidative stress

• Under normal condition, disruption of redox equilibrium Under normal condition, disruption of redox equilibrium by environmental or internal pro-oxidants triggers an by environmental or internal pro-oxidants triggers an adaptive response which results in up-regulation of adaptive response which results in up-regulation of antioxidant and cytoprotective enzymes and proteins. antioxidant and cytoprotective enzymes and proteins.

• In mammals, nuclear factor-erythroid 2 p45-related In mammals, nuclear factor-erythroid 2 p45-related factors 1 & 2 (Nrf2) regulates constitutive expression & factors 1 & 2 (Nrf2) regulates constitutive expression & orchestrates transcriptional up-regulation of genes orchestrates transcriptional up-regulation of genes encoding these cytoprotective molecules.encoding these cytoprotective molecules.

Nrf2/ARE pathwayNrf2/ARE pathway

Antioxidant proteins(e.g. GSTs, HO1)

ARE

Nucleus

Cytoplasm

Small Maf

Nrf2

Keap1

Actin

Reactive Oxygen Species (ROS)

Activation

Dissociation

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(A) 6 weeks

(B) 12 weeks

Impaired Nrf2 Activity in CRF kidney

Kim HJ, Vaziri ND. Am J Physiol Renal Physiol. 2010 Mar;298(3):F662-71.

NQO1

-actin

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Down-regulation of Nrf2 target gene products at 12 weeks

Kim HJ, Vaziri ND. Am J Physiol Renal Physiol. 2010

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Kim HJ, Vaziri ND. Am J Physiol Renal Physiol. 2010

Role of HDL deficiency & dysfunction in Role of HDL deficiency & dysfunction in CKD-associated oxidative stressCKD-associated oxidative stress

Anti-oxidant/Anti-atherogenic Actions of HDLAnti-oxidant/Anti-atherogenic Actions of HDL

A- Reverse cholesterol - lipid transportA- Reverse cholesterol - lipid transport

B- EC migration & endothelial repair (via SRB-1) B- EC migration & endothelial repair (via SRB-1)

C- Antioxidant/anti-inflammatory actionsC- Antioxidant/anti-inflammatory actionsaa. . ApoA-IApoA-I mediated extraction of oxidized mediated extraction of oxidized phospholipids phospholipids from lipoproteins and cell membranefrom lipoproteins and cell membrane

bb. . LCAT-LCAT-mediated hydrolysis of proinflammatory mediated hydrolysis of proinflammatory oxidized phospholipids (AA at sn-2)oxidized phospholipids (AA at sn-2)

cc.. Prevention of LDL oxidation and destruction of Prevention of LDL oxidation and destruction of oxidized phospholipids by oxidized phospholipids by paraoxonase-1paraoxonase-1 & & glutathione glutathione peroxidaseperoxidase (GPX) (GPX)

DD- Inactivation of PAF and PAF-like phospholipids by - Inactivation of PAF and PAF-like phospholipids by PAF acetyl PAF acetyl hydrolasehydrolase (anti-inflammatory / anti-thrombotic) (anti-inflammatory / anti-thrombotic)

LCAT

Liver

Bile

FC CE

SR-B1

ABCA1

HDL2 FC CE

ApoB100

SRA1LOX1CD36

Mature HDL Nascent HDL

HDL3

HDL- mediated Reverse Cholesterol Transport

& Anti-oxidant/anti-inflammatory actions

Ox-LDL

FC CEMacrophage

B chain ATP Synthase

LDL

ROS

PON

GPX

LCAT

ApoA1

Bile

HD

L

HDL CholesterolHDL Cholesterol ApoA-I

Glutathione peroxidase

ActivityActivity Concentration

Paraoxonase activityParaoxonase activity

HDL Antioxidant ActivityHDL Antioxidant Activity

Biomarkers of oxidative stress Biomarkers of oxidative stress byproducts of ROS interaction with bio-moleculesbyproducts of ROS interaction with bio-molecules

• Elevated plasma & tissue MDAElevated plasma & tissue MDA

• Elevated plasma, urine & tissue F2 isoprostaneElevated plasma, urine & tissue F2 isoprostane

• Elevated plasma & tissue nitrotyrosine (NO Elevated plasma & tissue nitrotyrosine (NO oxidation)oxidation)

• Increased Protein carbonyls & oxidized thiolsIncreased Protein carbonyls & oxidized thiols

• Increased plasma & urine oxidized nucleic acidsIncreased plasma & urine oxidized nucleic acids

• Elevated plasma and tissue advanced Elevated plasma and tissue advanced glycoxidation end products (AGE)glycoxidation end products (AGE)

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Markers of oxidative stress in CKD

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Protein CarbonylProtein Carbonyl

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ONOO- + Tyrosine nitrotyrosine

SummarySummary

• ROS production is markedly increased in the ROS production is markedly increased in the diseased kidneydiseased kidney

• Increased ROS production is accompanied by Increased ROS production is accompanied by impaired Nrf2 activation and consequent down-impaired Nrf2 activation and consequent down-regulation of the antioxidant & cytoprotective regulation of the antioxidant & cytoprotective moleculesmolecules

• Studies are underway to explore the effect of a Studies are underway to explore the effect of a potent Nrf2 activator in CKDpotent Nrf2 activator in CKD

Part 2- inflammation in CKD

Inflammation is invariably present in CKD

Link Between Oxidative Stress and Link Between Oxidative Stress and InflammationInflammation

Oxidative Oxidative StressStress

Antioxidant DepletionAntioxidant Depletion

↑ ↑ ROS ProductionROS Production

Leukocyte/MacrophageLeukocyte/MacrophageActivation (Inflammation)Activation (Inflammation)

NFNFκκB ActivationB Activation

Cytokines / ChemokinesCytokines / Chemokines

Ox LDL AGE

Ox PL

NFkB ActivationNFkB Activation

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Causes of CKD-associated inflammationCauses of CKD-associated inflammation

- Oxidative stressOxidative stress- Retained uremic metabolites & exogenous toxinsRetained uremic metabolites & exogenous toxins- Co-morbid conditions (e.g. diabetes and autoimmune - Co-morbid conditions (e.g. diabetes and autoimmune

diseases) diseases) - Infections (blood access, PD catheters, hepatitis etc)- Infections (blood access, PD catheters, hepatitis etc)- Iron overload - Iron overload - Hypervolemia / HypertensionHypervolemia / Hypertension- Increased pro-inflammatory properties of LDLIncreased pro-inflammatory properties of LDL- Impaired anti-inflammatory properties of HDLImpaired anti-inflammatory properties of HDL- Influx of impurities from dialysate compartmentInflux of impurities from dialysate compartment- Complement/leukocyte activation by dialyzer/pumpComplement/leukocyte activation by dialyzer/pump- - Influx of pro-inflammatory products from the GI Influx of pro-inflammatory products from the GI

tracttract

Role of the intestinal tract in the Role of the intestinal tract in the pathogenesis of inflammationpathogenesis of inflammation

Intestine and its barrier functionIntestine and its barrier function

• Although anatomically situated in the most central Although anatomically situated in the most central region of the body, the GI tract is actually an region of the body, the GI tract is actually an extension of the external environment within the extension of the external environment within the organism.organism.

• The primary functions of the intestine include: The primary functions of the intestine include: absorption of nutrientsabsorption of nutrients; ; secretion of waste secretion of waste products; products; & serving as a & serving as a barrierbarrier to prevent influx of microbes, to prevent influx of microbes, harmful microbial byproducts and other noxious harmful microbial byproducts and other noxious compounds into the host’s internal milieucompounds into the host’s internal milieu. .

Trans-cellular and paracellularTrans-cellular and paracellularepithelial barriers epithelial barriers

Intestinal epithelial barrier structure

Trans-cellular, cytosolic plaque, & acto-Trans-cellular, cytosolic plaque, & acto-myosin ring in TJ assembly myosin ring in TJ assembly

Evidence of the intestinal barrier dysfunction in Evidence of the intestinal barrier dysfunction in uremiauremia

• Presence of endotoxemia in uremic patients without detectable Presence of endotoxemia in uremic patients without detectable infection and its contribution to the prevailing systemic infection and its contribution to the prevailing systemic inflammation (inflammation (Gonçalves et alGonçalves et al, , 2006;2006; Szeto et al, 2008 Szeto et al, 2008))

• Increased intestinal permeability to high MW PEGs in the Increased intestinal permeability to high MW PEGs in the uremic humans and animals (uremic humans and animals (Magnusson et al, 1990,1991Magnusson et al, 1990,1991))

• Detection of luminal bacteria in mesenteric lymph nodes of the Detection of luminal bacteria in mesenteric lymph nodes of the uremic animals (uremic animals (de Almeida Duarte et al 2004 de Almeida Duarte et al 2004 ))

• Diffuse inflammation throughout the GI tract (esophagitis, Diffuse inflammation throughout the GI tract (esophagitis, gastritis, duodenitis, enteritis, colitis) in ESRD patients gastritis, duodenitis, enteritis, colitis) in ESRD patients maintained on dialysis (maintained on dialysis (Vaziri et al 1985Vaziri et al 1985))

HypothesisHypothesis

In view of the evidence for increased intestinal In view of the evidence for increased intestinal permeability in the uremic humans & animals permeability in the uremic humans & animals and the critical role of the epithelial tight and the critical role of the epithelial tight junction in the mucosal barrier function, I junction in the mucosal barrier function, I hypothesized that uremia may result in hypothesized that uremia may result in disruption of the intestinal tight junction disruption of the intestinal tight junction complexcomplex

Asc

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nDepletion of colonic tight junction proteins in uremia

Vaziri et al. Nephrol Dial Transplant. 2012 Jul;27(7):2686-93

Comparison of TJ protein expression between control rats and rats with CRF induced by 5/6 nephrectomy

Comparison of TJ protein expression between control rats and rats with CRF induced by adenine

Adenine induced-CKD model

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Figure 5Comparison of TJ protein mRNA expression between control and CRF rats

Conclusions of the TJ studiesConclusions of the TJ studies

- - Uremia results in disintegration of the Uremia results in disintegration of the intestinal epithelial tight junction complexintestinal epithelial tight junction complex

- This phenomenon can contribute to the - This phenomenon can contribute to the systemic inflammation and account for the systemic inflammation and account for the previously-demonstrated evidence of previously-demonstrated evidence of defective intestinal barrier function in defective intestinal barrier function in humans and animals with advanced CKDhumans and animals with advanced CKD

Role of lipoprotein abnormalities

Increased LDL pro-inflammatory activity and loss of HDL anti-inflammatory activity in

ESRD

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ESRD patients’ LDL is highly pro-inflammatory

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Treatment of CKD-associated oxidative stress

- All conventional therapies with proven efficacy in retarding CKD progression (i.e. RAS blockade , Glycemia & HTN control) reduce oxidative stress and inflammation

- Treatment with high doses of anti-oxidant vitamins are generally ineffective and may actually increase the risk of CVD and other complication

- Experimental therapies currently in clinical trial : I- AST-120, a specially formulated activated charcoal which limits absorption of the pro-oxidant gut–derived uremic toxins II- The Nrf2 activator, Bardoxolone, which can lower oxidative stress and inflammation by raising expression of endogenous antioxidant enzymes and related molecules

JPET # 175828

J Pharmacol Exp Ther 2011 Jun;337(3):583-90.

JPET # 175828

J Pharmacol Exp Ther 2011 Jun;337(3):583-90.

JPET # 175828

JPET # 175828

JPET # 175828

JPET # 175828

ConclusionsConclusions

CKD results in a vicious cycle of oxidative stress, inflammation and ER stress which work in concert to drive deterioration of kidney function and structure and contribute to the development and progression of CVD & many other complications

Acknowledgements

Dr Z. Ni, Dr Y. Bai

Dr Y. Ding, Dr XQ WangDr DC Zhan Dr R. SindhuDr C. Barton Dr J. ZhouDr M. Dicus Dr N. HoDr CY Lin Dr Z. LiF. Oveisi, F. FarbodA. Ehdai, L. SepassiDr K. Liang H.J. KimDt J Yuan Dr SubramanianDr Aminzadeh N. Goshtasbi

UCI

Korea

Dr. JR KooDr. CS LimDr JW Yoon

Venezuela

Dr B. Rodriguez-IturbeDr Y. QuirozDr M. Nava

UT SouthwesternDr. J. Zhou

UCLA

Dr M. Navab

Thank you