Download biographical sketch - Cardiovascular Research Training Program

OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)
BIOGRAPHICAL SKETCH
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NAME: Weinian
Shou
eRA COMMONS USER NAME (credential, e.g., agency login): [email protected]
POSITION TITLE: Professor
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency
training if applicable. Add/delete rows as necessary.)
INSTITUTION AND LOCATION
DEGREE
(if applicable)
Completion Date
MM/YYYY
FIELD OF STUDY
Wuhan University, China
B.S
07/1984
Cell Biology
Shanghai Institute of Cell Biology, China
Ph.D.
07/1991
Developmental Biology
M.D. Anderson Cancer Center, Houston, Texas
Postdoc
06/1994
Developmental Biology
Postdoc
10/1997
Mouse Genetics and
Developmental Biology
Baylor College of Medicine, Houston, Texas
A. Personal Statement
The major research focus undertaken in my lab is to determine the molecular signaling pathways involved in
the ventricular wall growth, maturation, and function in normal and various disease conditions using mouse
genetic manipulation. Oure current work evolves largely from our original discovery and characterization of
Bone Morphogenetic Protein 10 (BMP10) and related signaling pathways in ventricular trabeculation and
compaction. One of the important achievements in my career is the demonstration of the essential function
of BMP10 and its intracellular signaling pathway in controlling cardiomyocyte proliferation, ventricular wall
growth, trabeculation, and the pathogenesis of hypertrabeculation and the left ventricular noncompaction
(LVNC). Recent identification of that Daam1, as a part of non-canonical Wnt/PCP signaling pathway, plays
a critical role in ventricular wall compaction via the regulation of cardiomyocyte polarization and
myofibrillogenesis, further suggests a novel ventricular compaction pathway, which is independent of Bmp10mediated trabeculation pathway. We currently utilize mouse genetic tools and biochemical analyses to
determine the upstream signaling network that positively and negatively regulates Daam1 activities during
ventricular wall compaction, and test the hypothesis that altered Daam1 function and cell polarity and
myofibrillogenesis are common features in several LVNC mouse models as well as previously known
inherited cardiomyopathy models. In addition, our researches have also extended to channelopathies and
arrhythmia and signaling pathways involved in the heart failure.
B. Positions and Honors
Positions and Employment
1997 – 1999
Assistant Professor, Department of Molecular Physiology and Biophysics, Baylor
College of Medicine
1999 –2005
Assistant Professor of Pediatrics, Biochemistry & Molecular Biology, Medical &
Molecular Genetics, Indiana University School of Medicine (IUSOM)
2005 – 2010
Associate Professor (tenured) of Pediatrics, Biochemistry & Molecular Biology, Medical
& Molecular Genetics, Pharmacology & Toxicology, IUSOM
2010 – present
Professor of Pediatrics, Biochemistry & Molecular Biology, Medical & Molecular Genetics,
Pharmacology & Toxicology, IUSOM
Other Experience and Professional Memberships
2003-2008
Member, Cardiovascular Developmental Biology Study Section (National), AHA
2005
Ad hoc member, CDD, NIH.
2006
Ad hoc member, the Science Center Programs of the U.S. Department of State
2006-present
2007, 2008
2007
2007
2007-2013
2008, 2011
2008, 2011
2009
2009
2011
2012
2012-present
2012-present
2013
2015
2016-2021
Ad hoc reviewer, Chinese National Science foundation
Ad hoc reviewer, March of Dimes Foundation
Organizing Committee member, Weinstein Symposium for CV Development
Organizing Committee member, the first International Conference for Biocomplexity
Editorial Board Member, Journal of Biological Chemistry
Co-editor, special issue for cardiac development, Journal of Pediatric Cardiology
Co-Organizer, 2008 Riley Heart Research Symposium
Ad hoc reviewer, International Foundation for Cancer Research
Ad hoc member, NIHLB, Special review panel for Stem Cell Research
Ad hoc member, NIHLB, Special review panel for conferences
Ad hoc member, NIDDK, Special review panel for DKUS
Member, Cardiovascular Developmental Biology Review Panel, AHA
Associate Editor, Pediatric Cardiology
External Expert Member, French National Research Agency
Ad hoc member, NIHLB, Special review panel for conferences
Editorial Board Member, Journal of Biological Chemistry
C. Contribution to Science: In the past, we have published total of 86 peer-reviewed articles (the full list see:
http://www.ncbi.nlm.nih.gov/sites/myncbi/weinian.shou.1/bibliography/41165468/public/?sort=date&direction=ascending ) and
8 book chapters. Major contributions are in five research areas:
1) Identification of cardiac cytokine BMP10 and demonstration of its function in regulating ventricular
wall growth at mid-gestation stage (Partially relevant to the current proposal)
Ventricular trabeculation and compaction are two critical morphogenetic processes during ventricular wall
development and maturation. When either of the processes is disrupted, a unique cardiomyopathy, named the
left ventricular noncompaction (LVNC), will develop. Despite LVNC was known in clinic for over a century, its
etiology and pathogenesis pathway are poorly understood. My lab was among the first to create a LVNC-model
in mice (Nature 1998). To determine the molecular mechanism underlying LVNC, we used a RNA-differential
display technique and were able to identify Bone Morphogenetic Protein 10 (BMP10) as a novel target
(Development, 2004). Among over 30 different members of TGF/BMP superfamily, BMP10 is unique for its
restricted expression pattern in the developing heart and in the trabecular myocardium. Subsequently, we were
able to demonstrate that BMP10 is a critical cytokine in regulating ventricular wall growth at mid-gestation stage
(Cell, 2004; JBC, 2006; JBC 2011). In addition, we have identified that endothelial Notch1 activity is a key upstream regulator of BMP10 and neuregulin 1 (Development Cell 2007; Development. 2013) and Tbx20 is a key
BMP10 down-stream factor (JBC 2011). Collectively, these studies demonstrated for the first time that altered
ventricular wall growth is likely a key contributor to LVNC phenotype, which was later supported by numerous
studies and other LVNC animal models.
a) Shou W, Aghdasi B, Armstrong DL, Guo Q, Bao S, Charng M, Mathews LS, Schneider MD, Hamilton SL,
Matzuk MM. Cardiac defects and altered ryanodine receptor function in FKBP12-deficient mice. Nature
391:489-492, 1998. PMID 9461216
b) Chen H, Shi S, Acosta L, Li W, Lu J, Bao S, Chen Z, Yang Z, Schneider MD, Chien KR, Conway SJ,
Yorder MC, Haneline L, Franco D and Shou W. BMP-10 is essential for cardiac growth regulation at
midgestation. Development 131 (9): 2219-2231, 2004. PMCID2628765
c) Pashmforoush M, Lu JT, Chen H, Kondo R, Evans S, Clark B, Feramisco JR, Amand T, Giles W, Ho SY,
Benson DW, Silberbach M, Shou W and Chien KR. Nkx2.5 pathways and congenital Heart disease: Loss
of ventricular myocyte lineage specification leads to progressive cardiomyopathy and completeheart block.
Cell 117: 373-386, 2004. PMID: 15109497
d) Chen Q, Chen H, Zheng D, Zhu W, Bu G, Zhang X, Chen J, Field LJ, Rubart M, Shou W* and Chen Y.
Smad7 is required for the development and function of heart. JBC, 284(1):292-300. 2009. PMCID2610499
*Co-Corresponding author
e) Zhang W, Chen H, Wang Y, Yong W, Zhu W, Liu Y, Wagner GR, Payne RM, Field LJ, Xin H, Cai CL, Shou
W. Tbx20 a downstream mediator for bone morphogenetic protein 10 in regulating cardiac ventricular wall
development and function. JBC 286(42):36820-36829, 2011. PMCID3196085
f) Chen H, Zhang W, Sun X, Yoshimoto M, Chen Z, Zhu W, Liu J, Shen Y, Yong W, Li D, Zhang J, Lin Y,
VanDusen NJ, Snider P, Schwartz RJ, Conway SJ, Field LJ, Yoder MC, Firulli AB, Carlesso N, Towbin JA,
Shou W. FKBP12 controls ventricular myocardium trabeculation and compaction via regulating endocardial
Notch1 activity. Development 140:1946-1957. 2013. PMCID3631969
2) Demonstrating DAAM1 and Wnt-PCP signaling in regulating ventricular wall maturation at midgestation stage (Not relevant to the current proposal).
Relevant to the current proposal, we discovered that dishevelled associated activator of morphogenesis
(DAMM1) is dramatically down-regulated in LVNC hearts. We have generated DAAM1-deficient mice and we
are able to demonstrate that DAAM1 is a critical non-canonical Wnt-PCP signaling component and plays a critical
role in cardiomyocyte myofibrillogenesis, polarization, cell-cell alignment, which are important to myocardial
maturation during mid-gestation development (Development 2011). Interestingly, in this model, LVNC phenotype
is independent of cardiomyocyte proliferation, suggesting another signaling pathway contributing to LVNC
pathogenesis (Am J. Med Genet Part C: Seminars in Medical Genetics 2013). Collectively, these data strongly
support a working model in which two distinct genetic pathways are involved in the regulation of ventricular
trabeculation and compaction. The BMP10-mediated cascade serves as a key regulator for cardiomyocyte
proliferation and ventricular trabeculation/compaction, while Wnt/PCP-mediated modulation of the Daam1
pathway serves as a key regulator of cardiomyocyte myofibrillogenesis and polarity that allows for ventricular
compaction.
a) Li D, Hallett MA, Zhu W, Rubart M, Liu Y, Yang Z, Chen H, Haneline LS, Chan RJ, Schwartz RJ, Field LJ,
Atkinson SJ, Shou W. Dishevelled associated activator of morphogenesis (DAMM1) is required for heart
morphogenesis. Development, 138(2): 303-315. 2011. PMCID3005605
b) Zhang W, Chen H, Qu X, Chang C-P, Shou W. Molecular mechanism of ventricular trabeculation
/compaction and the pathogenesis of the left ventricular noncompaction cardiomyopathy (LVNC). Am J.
Med Genet Part C: Seminars in Medical Genetics 163(3):144-156. 2013. PMCID3725649
3) Demonstration of FKBP12 and FKBP12.6 is an important functional regulator for voltage-gated
sodium channel, ryanodine receptor, and cardiac arrhythmia (relevant to the current proposal).
Cardiac voltage-gated Na+ channels determine the amplitude and slope of the action potential upstroke in
atrial and ventricular cardiomyocytes and are responsible for the generation of the inward sodium current that
underlies excitability and conduction in working myocardium and conduction system cells. Mutations in genes
encoding cardiac voltage-gated Na+ channels SCN5A and their functional regulators are associated with multiple
forms of arrhythmogenic syndromes. We identified a novel physiological function for FKBP12 in regulating
cardiac voltage-gated Na+ channels. Previously, it was shown that FKBP12 regulates the skeletal muscle Ca2+
release channel RYR1 and excitation-contraction (E-C) coupling in skeletal muscle. However, its function in
cardiomyocytes is largely unknown, despite that FKBP12 is highly expressed in cardiomyocytes. Our results
demonstrated that FKBP12 is an essential regulator of cardiac voltage-gated Na+ channels and that FKBP12 is
critical for cardiac arrhythmogenesis (Circulation Research 2011), which is different from FKBP12.6 in regulating
Ca2+ release channel RYR2 (Assay and Drug Development Technologies 2011). Furthermore, we analyzed a
human Nav1.5 mutation represented clinic manifestation similar to FKBP12 transgenic mice and demonstrated
physiological characteristics of the mutant channel (J Physiol 2012). Collectively, these data defined the
physiological function of FKBP12 in the heart and its contribution to arrhythmias and clarified functional
differences of FKBP12 and FKBP12.6.
a) Maruyama M, Li B, Chen H, Xu X, Song L-S, Zhu W, Yong W, Bu G-X, Lin S-F, Fishbein MC, Lederer WJ,
Schild JH, Field LJ, Rubart M, Chen P-S, Shou W. FKBP12 is a critical regulator of the heart rhythm and the
cardiac voltage-gated sodium current in mice. Circulation Research 108: 1042-1052, 2011. PMCID3092589
b) Song W, Xiao Y, Chen H, Ashpole N, Piekarz AD, Ma P, Yong W, Hudmon A, Cummins TR, Shou W.
Human Nav1.5 F1486 deletion associated with long DT syndrome leads to deficiency in inactivation and
reduces lidocaine sensitivity. Journal of Physiology 2012, 590(Pt 20):5123-39. PMCID3497567
c) Liu Y, Chen H, Ji G, Li B, Mohler PJ, Zhu Z, Yong W, Chen Z, Xu X, Xin H, Shou W. Transgenic analysis of
the role of FKBP12.6 in cardiac function and intracellular calcium release. Assay and Drug Development
Technologies 2011 9(6):620-7. PMCID3232634
4) Characterization of plakoglobin (-catenin) in the pathogenesis of arrhythmogenic right ventricular
cardiomyopathy (ARVC) (not relevant to the current proposal).
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inheritable myocardial disorder associated
with fibrofatty replacement of myocardium and ventricular arrhythmia. A subset of ARVC is categorized as Naxos
disease, which is characterized by ARVC and a cutaneous disorder. A homozygous loss-of-function mutation of
the Plakoglobin (Jup) gene, which encodes a major component of the desmosome and the adherens junction,
had been identified in Naxos patients, though the underlying mechanism remained elusive. We generated Jup
mutant mice by ablating Jup in cardiomyocytes. Jup mutant mice largely recapitulated the clinical manifestation
of human ARVC: ventricular dilation and aneurysm, cardiac fibrosis, cardiac dysfunction and spontaneous
ventricular arrhythmias (Hum Mol Genet 2011). Ultra-structural analyses revealed that desmosomes were absent
in Jup mutant myocardia, whereas adherens junctions and gap junctions were preserved. Despite the increase
of β-catenin at adherens junctions in Jup mutant cardiomyoicytes, the Wnt/β-catenin mediated signaling was not
altered. TGFβ mediated signaling was found significantly elevated in Jup mutant cardiomyocytes at the early
stage of cardiomyopathy, suggesting an important pathogenic pathway for Jup-related ARVC. Additional analysis
also demonstrated its role in epithelial cell function and tissue homeostasis (JBC 2012). Collectively, these
findings have provided further insights for the pathogenesis of ARVC and potential therapeutic interventions.
a) Li D, Liu Y, Maruyama M, Zhu W, Chen H, Zhang W, Reuter S, Lin SF, Haneline LS, Field LJ, Chen PS,
Shou W. Restrictive loss of plakoglobin in cardiomyocytes leads to arrhythmogenic cardiomyopathy. Hum
Mol Genet 20(23):4582-4596, 2011. PMCID3209829
b) Li D, Zhang W, Liu Y, Haneline LS, Shou W. Lack of Plakoglobin in epidermis leads to keratoderma. JBC
287(13):10435-43. 2012. PMCID3322998
5) Identification of cardiac cytokine BMP10 as a cardioprotective factor in postnatal heart (not relevant
to the current proposal).
We characterized that BMP10 and BMP9 are functional redundant in regulating vasculature development
(PNAS 2013). However, a novel unexpected biological function of BMP10 in postnatal heart is its activity in
preventing adult cardiomyocyte cell death. By analyzing BMP10-trangenic mice (JBC 2006), we were able to
demonstrate that BMP10 exhibits a strong activity in maintaining cardiomyocyte survival and preventing cardiac
fibrosis in postnatal heart in response to various insults (e.g., doxorubicin-mediated cardiotoxicity), which
provides a potential novel therapy for injured heart (Patent: US2012-0093776 A1, issued: Nov 2014). Recent
analysis further demonstrated that this cardioprotective activity of BMP10 is in part via its non-canonical function
in activating Stat3 (in addition to its canonical Sma1/5/8 activation). Special efforts are undertaken to develop
small molecules mimicking BMP10 activity in cardioprotection.
a) Chen H, Brady J, Sai T, Lai J, Warming S, Chen H, Roose-Girma M, Zhang G, Shou W and Yan M.
Context-dependent signaling defines dual functions of BMP10 during embryonic development. PNAS 2013,
110(29):11887-92. PMCID3718114
b) Shou W, Chen H, Field LJ Patent: US2012-0093776 A1, issued: Nov 2014
c) Zhang W, Qu X., Chen B, Snyder M, Wang M, Li B, Tang Y, Chen H, Zhu W, Zhan L, Yin N, Li D, Li X, Liu
Y, Zhang J, Fu X-Y, Rubart M, Song L-S, Huang X-Y, Shou W. Critical Roles of Stat3 in -adrenergic
functions in the heart. Circulation 133(1):48-61. 2016. PMCID4698100
D. Research Support
Active
R01HL120920 (PI: Anthony Firulli; Co-PI: Weinian Shou)
09/01/13-08/31/17
NIH/NHLBI
Endocardial mechanisms of cardiac trabeculation and septation.
The major goals are to investigate how Hand2-mediated transcriptional regulation to ventricular wall
development and the contribution to congenital heart defect.
R01HL122123 (PI: Anthony Firulli; Co-PI: Weinian Shou)
09/01/13-08/31/17
NIH/NHLBI
Cellular and molecular mechanisms of left ventricular growth and morphogenesis.
The major goals are to investigate how Hand1-mediated transcriptional regulation to left ventricular growth
during development. No overlap with current application
P01HL134599 (Project 3 PI Weinian Shou)
11/01/17-10/31/22
NIH/NHLBI
The major goals are to investigate the signaling in the morphogenesis and growth of the ventricular wall during
development and pathogenesis leading to disease states.
Completed in the past 3 years:
R01HL81092 (PI: Weinian Shou)
07/01/07-06/30/12
NIH/NHLBI
Molecular pathway in myocardium development.
The major goals are to investigate the molecular mechanism by which regulates ventricular wall formation and
maturation.