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Oxidative Stress and Inflammation in Chronic Kidney Disease: The Nature, Mechanisms, Consequences and Treatment. N. D. Vaziri M.D., MACP Division of Nephrology and Hypertension University of California Irvine, Irvine. Part 1- Oxidative Stress in CKD. - PowerPoint PPT Presentation
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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
Cox-1
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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
Nrf2 P
Nrf2 P
Small Maf Nrf2 P
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Nrf2
Histone H1
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-actin
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-actin
*
(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
HO-1
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-actin
Down-regulation of Nrf2 target gene products at 12 weeks
Kim HJ, Vaziri ND. Am J Physiol Renal Physiol. 2010
Mn-SOD
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-actin
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-actin
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-actin
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-actin
Nrf2 target gene products at 12 weeks
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)
CTL CRF
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Markers of oxidative stress in CKD
Urine 8-hydroxy-2'-deoxyguanosine excretion
8-ox
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Protein CarbonylProtein Carbonyl
O2- +NOONOO- (peroxynitrite)
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
NFkB activation
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PAI-1
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
end
ing
colo
nD
esce
nd
ing
colo
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
0
0.5
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2.0
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p=0.003
Normal LDL
Uremic LDL
Infla
mm
ator
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dex
LDL
____
ESRD patients’ LDL is highly pro-inflammatory
0
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LDL +Normal HDL
LDL+ uremic HDL
HD
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p=0.001
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