PHA Gabrielle Miyara & Rachel Hoyt Memorial Proof of Concept Research Grant Winner 2012

Guofei ZhouGuofei Zhou, PhD

Department of Pediatrics and University of Illinois Cancer Center
University of Illinois College of Medicine, Chicago
Title: "AMPK and Pulmonary Arterial Hypertension"
Term: December 1, 2012 through November 30, 2013

Summary of Research Project:

Pulmonary Artery Hypertension (PAH) is a devastating disease with long-term morbidity and mortality. Pulmonary artery smooth muscle cells (PASMC) cause the development and progression of high pulmonary vascular tone observed in PAH patients. Although it is well established that PASMC contribute to pulmonary artery remodeling during the pathogenesis of PAH, the molecular mechanisms underlying the survival of PASMC remains unclear. Hypoxia, a well-known cause of PAH, activates adenosine monophosphate protein kinase (AMPK) in some cells. Our study investigates whether AMPK plays a role in the survival of PASMC during hypoxia. We hypothesize that activation of AMPK during hypoxia prevents apoptosis and induces autophagy, resulting in the survival of PASMC and the development of PAH.

Our studies suggest that AMPK may be a novel therapeutic target for the treatment of PAH. Completion of the proposed studies will provide novel insights into the understanding of pathogenesis of PAH, which may result in the development of innovative approaches for the treatment of patients with this disease.

Curriculum Vitae

NAME: Guofei Zhou, PhD
POSITION TITLE: Assistant Professor in Pediatrics, University of Illinois at Chicago

Education

1999-2004 PhD, University of South Alabama College of Medicine Department of Biochemistry and Molecular Biology, Mobile, Al, USA.
1995-1998 Master of Science, Shanghai Medical University Department of Biochemistry, Shanghai, China.
1986-1990 Bachelor of Science, Peking University Department of Biology, Beijing, China.

 

Positions and Employment

2008-present Assistant Professor, University of Illinois at Chicago Department of Pediatrics, University of Illinois at Chicago Cancer Center
2008 Research Assistant Professor, Northwestern University Division of Pulmonary and Critical Care Medicine
2004-2008 Postdoctoral Fellow, Northwestern University Division of Pulmonary and Critical Care Medicine
1999-2004 Research Assistant, University of South Alabama, College of Medicine Department of Biochemistry and Molecular Biology
1998-1999 Lecturer, Zhejiang Ocean University
1995-1998 Lecturer, Zhoushan Teacher’s College
1990-1995 Research/Teaching Assistant, Zhoushan Teachers’ College
1989-1990 Research Assistant, Peking University

 

Other Experience and Professional Memberships

2004-present American Heart Association
2004-present American Thoracic Society
2004-present American Society for Biochemistry and Molecular Biology
2011-present American Association for Cancer Research
2004 Instructor for BEAR (Biomedical Enrichment and Recruitment) program, University of South Alabama, Mobile, AL.
2006 Analytical and Quantitative Light Microscopy Course, Marine Biological Laboratory, Woods Hole, MA
2008-present Reviewer, PLoS ONE
2007-present Reviewer, Faseb J
2009-present Reviewer, The American Journal of Physiology - Lung Cellular and Molecular Physiology
2010-present Reviewer, Molecular Cancer
2010-present Reviewer, American Journal of Respiratory and Critical Care Medicine
2012-present Reviewer, Molecular and Cellular Biology
2012 Faculty judge for the 2012 UIC Student Research Forum
2012-present Reviewer, Yonsei Medical Journal

 

Teaching Experiences

2010 Cell Biology Series, Neonatal-perinatal fellowship Program, University of Illinois at Chicago Department of Pediatrics
2004 Summer BEAR (Biomedical Enrichment and Recruitment) program, University of South Alabama, Mobile, AL. The BEAR Program represents an additional opportunity for underrepresented students to enter medical school at USA.
1998-1999 Teaching Botany & lab and Biochemistry for undergraduate students at Zhejiang Ocean University
1990-1995 Teaching Botany & lab, Biochemistry, and Genetics for undergraduate students at Zhoushan Teachers’ College

 

Honors

1997   Guanghua Scholarship, Shanghai Medical University Graduate School
2002-2004 American Heart Association Pre-doctoral Fellowship
2004 Shanghai Medical Science & Technology Award
2008 Travel grant to American Thoracic Society 2008 International Conference at Toronto
2006-2009 Parker B. Francis Research Award
2009 NIH Young Investigator Award
2008-2009 Excellence in ASCEND Scholars Program, University of Illinois at Chicago

 

Students, research staff, and postdoctoral fellows trained
Dr. Aarti Raghavan, 2/1/2009-6/30/2010. Currently she is an attending physician and Assistant Professor of Clinical Pediatrics at the University of Illinois at Chicago.

Dr. Joyce Christian F. Ibe, 7/1/2009-present, University of Illinois at Chicago neonatal-perinatal fellowship program

Dr. Xiangli Meng, 2010. Currently she is Director of Strategy and Development at the Frontier Institute of Science and Technology (FIST), Xi’an Jiaotong University.

Dr. Tianji Chen, 11/1/2010-present.

Dooniya Shaikh, 2008-2011, University of Illinois at Chicago Honors College

Dr. Harini Racherla, 9/1/2009-5/30/2010, Pediatrics resident

Mrs. Qiyuan Zhou, 12/2008-current, research specialist, University of Illinois at Chicago Department of pediatrics.

Iryna Shak, 9/012012-5/30/2013, Undergraduate, University of Illinois at Chicago

Syed Raza Jafri, 9/012012-5/30/2013, Undergraduate, University of Illinois at Chicago

Publications

1.   Shi DJ, Zhou G. Studies on photosynthesis, respiration, and morphology of Nostoc Flagelliforme, Acta Botanica Sinica, 34(7): 507-514,1992 (in Chinese)

2.   Zhou G, Primary study on ecology of Egretta intermedia and Larus crassirotris in Zhoushan Wuzishan Island, Chinese Journal of Zoology, 29(1): 31-33,1994 (in Chinese)

3.   Zhou G. Cell cycle and tumorous chemotherapy, Journal of Biology, 13(7): 11-12,1996 (in Chinese)

4.   Zhou G, Zha XL. Progress in integrin and apoptosis research, Chemistry of Life, 17(2): 32-34,1997, review (in Chinese)

5.   Zhou G, Fan Q, Feng Y, Ge H, Zha XL. Establishment and Identification of SMMC7721 cell lines with over-expression of integrin a5b1,J Shanghai Med Univ, 26(3): 161-164,1999 (in Chinese)

6.   Zhou G, Zha X. Detection of mRNA Expression of Integrin a5b1 on SMMC 7721 Human Hepatocellular Caricinoma Cell Line with RT-PCR Method, Journal of Zhejiang Ocean University (Natural Sciences), 2000;19(2):109-113.

7.   Zhou G, Feng Y, Cao LH, Zha XL. Over expression of integrin a5b1 in human hepatocellular carcinoma cell line suppresses cell proliferation in vitro and tumorigenicity in nude mice, Mol Cell Biochem 2000;207:49-55.

8.   Fang XC, Su JM, Zhou G, Zha XL. Effect of integrin a5b1 gene overexpression on cell adhesion and migration in hepatocellular carcinoma cell line. China Oncology, 2001;11(1):1-4.

9.   Feng Y, Wang LY, Cai T, Jin JW, Zhou G, Cao LH, Zha XL. All-trans-Retinoic Acid Increased the expression of Integrin alpha5 teba1 and Induced 'anoikis' in SMMC-7721 Hepatocarcinoma Cell. J Exp. Clin. Cancer Res. 2001;20(3):203-212.

10. Golden T, Aragon IV, Zhou G, Cooper SR, Dean NM, Honkanen RE. Constitutive over expression of serine/threonine protein phosphatase 5 (PP5) augments estrogen-dependent tumor growth in mice. Cancer Lett. 2004;215(1):95-100.

11. Zhou G, Golden T, Aragon IV, Honkanen RE. Ser/Thr protein phosphatase 5 inactivates hypoxia-induced activation of an apoptosis signal-regulating kinase 1/MKK-4/JNK signaling cascade. J Biol Chem. 2004;279(45):46595-605.

12. Lecuona E, Dada L, Sun H, Butti ML, Zhou G, Chew T, Sznajder JI. Na,K-ATPase alpha1-subunit dephosphorylation by protein phosphatase 2A is necessary for its recruitment to the plasma membrane. FASEB J. 2006;20(14):2618-20.

13. Dada LA, Welch LC, Zhou G, Ben-Saadon R, Ciechanover A and Sznajder JI, Phosphorylation and ubiquitination are necessary for Na,K-ATPase endocytosis during hypoxia. Cell Signal. 2007;19(9):1893-8.

14. Golden T, Aragon IV, Rutland B, Tucker JA, Shevde LA, Samant RS, Zhou G, Amable L; Skarra D, Honkanen RE. Elevated levels of ser/thr protein phosphatase 5 (PP5) in human breast cancer. Biochim Biophys Acta. 2008; 1782(4):259-70.

15. Zhou G, Dada LA, Chandel NS, Iwai K, Lecuona E, Ciechanover A, Sznajder JI. Hypoxia-mediated Na,K-ATPase degradation requires von Hippel Lindau protein. FASEB J. 2008; 22(5):1335-42.

16. Zhou G, Dada LA, Sznajder JI. Regulation of alveolar epithelial function by hypoxia. Eur Respir J. 2008; 31(5):1107-13.

17. Zhou G, Dada LA, Wu M, Kelly A, Trejo H, Zhou Q, Varga J, Sznajder JI.Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1. Am J Physiol Lung Cell Mol Physiol. 2009; 297(6): L1120-30.

18. Zhou Q, Pardo A, Koenigshoff M, Eickelberg O, Budinger GRS, Thavarajah K, Gottardi CJ, Jones J, Varga J, Selman M, Sznajder JI, Raj JU, Zhou G*. Role of von Hippel-Lindau protein in fibroblast proliferation and fibrosis. FASEB J. FASEB J. 2011 Sep;25(9):3032-44. Epub 2011 Jun 3. * Corresponding author

19. Zhou Q, Chen T, Ibe JC, Raj JU, Zhou G*. Loss of either hypoxia inducible factor 1 or 2 promotes lung cancer cell colonization. Cell Cycle. 2011 Jul 1;10(13). [Epub ahead of print]. * Corresponding author

20. Raghavan A, Zhou G *, Zhou Q, Ibe JC, Ramachandran R, Racherla H, Raychaudhuri P, Raj JU. Hypoxia-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation Is Controlled by Forkhead Box M1 Am J Respir Cell Mol Biol. 2012 Apr;46(4):431-6. * Corresponding author

21. ShaikhD, Zhou Q, IbeJCF, Chen T, RajJU, Zhou G*. cAMP-dependent protein kinase is essential for hypoxia-mediated epithelial-mesenchymal transition, migration, and invasion in lung cancer cells. Cell Signaling (Accepted). * Corresponding author

22. Zhou Q, Chen T, Ibe JCF, Raj JU, Zhou G*. Knockdown of von Hippel-Lindau Protein decreases lung cancer cell proliferation and colonization. FEBS Lett. 2012 May 21;586(10):1510-5. Epub 2012 Apr 20. * Corresponding author

23. Gou D, Ramchandran R, Peng X, Yao L, Kang K, Sarkar J, Wang Z, Zhou G, Raj JU.miR-210 has an anti-apoptotic effect in pulmonary artery smooth muscle cells during hypoxia. Am J Physiol Lung Cell Mol Physiol. 2012 Aug 10. [Epub ahead of print]

Book Chapter

Zhou G, Dada LA, Sznajder JI. Regulation of Na,K-ATPase by Reactive Oxygen Species. Current Topics in Membranes, Volume 61, P133-148, 2008: Free Radical Effects on Membranes. Editor: Dr. Sadis Matalon; Publisher: Elsevier

Published Abstracts

Qiyuan Zhou, Tianji Chen, Joyce Christina F. Ibe, J. Usha Raj, Guofei Zhou. Deletion of von Hippel-Lindau protein in fibroblasts protects against bleomycin-induced pulmonary fibrosis. American Thoracic Society International Conference, 2012 San Francisco.

Tianji Chen, Guofei Zhou, Qiyuan Zhou, Joyce Christina F. Ibe, Suzy A. Comhair, Serpil C. Erzurum, J Usha Raj. miR-17~92 regulates differentiation of pulmonary arterial smooth muscle cells via a TGF-β dependent pathway. American Thoracic Society International Conference, 2012 San Francisco.

Joyce Christina F. Ibe, Guofei Zhou, Qiyuan Zhou, Tianji Chen, J. Usha Raj. Adenosine Monophosphate-Activated Protein Kinase Α2 Is Critical For The Survival Of Human Pulmonary Artery Smooth Muscle Cells During Hypoxia. American Thoracic Society International Conference, 2012 San Francisco.

Qiyuan Zhou, Tianji Chen, Joyce Christina F. Ibe, J Usha Raj, Guofei Zhou. Downregulation of PKCζ/par3/par6 polarity complex is critical for hypoxia-induced epithelial-mesenchymal transition, migration, and invasion in lung cancer cells. American Association for cancer Research Annual meeting, 2012, Chicago, IL.

J.C.F. Ibe, Q. Zhou, A. Raghavan, G. Zhou, J.U. Raj.  Differential Roles of Adenosine Monophosphate‐Activated Protein Kinase Α1 And Α2 in Hypoxia‐Mediated Survival of Human Pulmonary Artery Smooth Muscle Cells University of Illinois at Chicago College of Medicine Research Forum, 2011, Chicago, IL, the United States.

A. Raghavan, Q. Zhou, J.C.F.  Ibe, R. Ramachandran, H. Racherla, P. Raychaudhuri, G. Zhou, J. U. Raj. Hypoxia mediates pulmonary artery smooth muscle cell proliferation via the HIF/Forkheadbox M1 pathway. University of Illinois at Chicago College of Medicine Research Forum 2011, Chicago, IL, the United States.

Dooniya Shaikh, Qiyuan Zhou, Aarti Raghavan, J Usha Raj, Guofei Zhou, cAMP-dependent protein kinase is essential for hypoxia-mediated epithelial-mesenchymal transition, migration, and invasion in lung cancer cells. University of Illinois at Chicago Research Forum, 2011, Chicago, IL, the United States. 3rd place in the life sciences category.

Qiyuan Zhou, J Usha Raj, Guofei Zhou, Role of VHL and HIF in Lung Cancer Metastasis. American Thoracic Society International Conference, 2011 Denver.

J.C.F. Ibe, Q. Zhou, A. Raghavan, G. Zhou, J.U. Raj.  Differential Roles Of Adenosine Monophosphate-Activated Protein Kinase Α1 And Α2 In Hypoxia-Mediated Survival Of Human Pulmonary Artery Smooth Muscle Cells. Pediatric Academic Societies, Denver, 2011.

A. Raghavan, Q. Zhou, J.C.F.  Ibe, R. Ramachandran, H. Racherla, P. Raychaudhuri, G. Zhou, J. U. Raj. Hypoxia mediates pulmonary artery smooth muscle cell proliferation via the HIF/Forkheadbox M1 pathway. American Thoracic Society International Conference, 2011, Denver.

Shaikh D, Zhou Q, Raghavan A, Raj JU, Zhou G. cAMP-dependent protein kinase is essential for hypoxia-mediated epithelial-mesenchymal transition, migration, and invasion in lung cancer cells. American Thoracic Society International Conference, 2010, New Orleans.

Queisser MA, Zhou G, Dada LA, Sznajder JI. Role of protein kinase C zeta (PKCz) in the Na,K-ATPase regulation during hypoxia. American Thoracic Society International Conference, 2010, New Orleans.

A. Raghavan, H. Racherla, R. Ramachandran, J.C.F.  Ibe, P. Raychaudhuri, G. Zhou, J. U. Raj. Forkheadbox M1 is necessary for hypoxia-mediated proliferation of Pulmonary artery smooth muscle cells. Pediatric Academic Societies, Vancouver, May 2010. (Platform presentation).

A. Raghavan, H. Racherla, R.Ramachandran, P. Raychaudhuri, G. Zhou, J. U. Raj. Hypoxia promotes pulmonary artery smooth muscle cells through induction of FoxM1.
75th Perinatal & Developmental Medicine Symposium. American Academy of Pediatrics Section on Perinatal Pediatrics. Marco Island, November 2009. (Platform presentation).

A. Raghavan, H. Racherla, R. Ramachandran, P. Raychaudhuri, G. Zhou, J. U. Raj. Hypoxia promotes proliferation of pulmonary artery smooth muscle cells through induction of FoxM1 by Hypoxia Inducible Factor. 50th Annual Midwest Society for Pediatric Research Scientific Meeting, Chicago,  October 2009 (Platform presentation).

A. Raghavan, H. Racherla, R.Ramachandran, P. Raychaudhuri, G. Zhou, J. U. Raj. Hypoxia promotes pulmonary artery smooth muscle cells through induction of FoxM1.
33rd Midwest Perinatal Research Conference – Hueston Woods, September 2009 (Platform presentation).

Sarkar J, Turaka P, Gou D, Ramchandran R, Zhou G, Raghavan A and Raj JU. MiR-21 plays a role in smooth muscle cell proliferation induced by hypoxia. Experimental Biology 2009, New Orleans, Louisiana.

Zhou G, PardoA, Koenigshoff M, DadaLA, Eickelberg O, Varga J, SelmanM and Sznajder JI. Elevated levels of von Hippel-Lindau protein in human and mouse fibrotic lungs. Experimental Biology 2009, New Orleans, Louisiana.

Zhou G, PardoA, Koenigshoff M, DadaLA, Eickelberg O, BudingerGRS, Thavarajah K, Gottardi CJ, Jones J, Varga J, SelmanM and Sznajder JI. Mouse and human fibrotic lungs express higher levels of von Hippel-Lindau protein. 2009 Keystone fibrosis symposium, Keystone, Colorado.

Zhou G, Dada L, Wu M, Kelly A, Varga J, Sznajder JI. Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and TGFb signaling. American Thoracic Society International Conference, 2008, Toronto.

Zhou G, Dada LA, Lecuona E, Sznajder JI. PKCz is necessary in von Hippel-Lindau protein-mediated degradation of Na,K-ATPase. American Thoracic Society International Conference, 2007 San Francisco.

Zhou G, Dada L, Lecuona E, Comellas A, Bell E, Chandel N, Ciechanover A, and Sznajder JI. Hypoxia-mediated Degradation of Na,K-ATPase is von ippel-Lindau Protein Dependent but HIF Independent. American Thoracic Society International Conference, 2006 San Diego.

Vadasz I, Dada L, Lecuona E, Welch L, Briva A, Chen J, Zhou G, Seeger W, Sznajder JI. Hypercapnia-induced Endocytosis of Na,K-ATPase is Mediated by c-Jun N-terminal kinase. American Thoracic Society International Conference, 2006 San Diego.

Zhou G, Golden T, Honkanen RE. Identification of a hypoxia-inducible factor 1(HIF1) regulated protein phosphatase that acts to suppress apoptotic cell death. Supplement to Circulation, 106 (19), 1112, 75th American Heart Association Scientific Sessions, Nov. 17-20, 2002, Chicago (Oral Presentation).

Zha XL, Zhou G, Feng Y. Over expression of integrin a5b1 suppresses the malignant phenotype of human hepatocellular carcinoma cell, Sino-Canadian Symposium on Recent Advances in Cardiovascular and gastrohepatic Research, Nov 30-Dec 2, 1998, Robert Black College, Canada.

Research Support
Active Research Support

American Thoracic Society/Pulmonary Hypertension Association Proof-of-Concept Award, $27,500,10/1/2012-9/30/2013.
"AMPK and pulmonary arterial hypertension." 
This project is to investigate that AMPK may be a novel therapeutic target for the treatment of PAH and completion of the proposed studies will provide novel insights into the understanding of pathogenesis of PAH, which may result in the development of innovative approaches for the treatment of patients with this disease.
Role: Principle Investigator 

1R03HL110829-01, $159126, 09/23/2011- 07/31/2013.
"MicroRNAs in Regulation of Pulmonary Vascular Smooth Muscle Cell Proliferation."
The goal of this project is to identify dysregulated miRNAs in pulmonary arterial smooth muscle cells isolated from patients with idiopathic pulmonary hypertension and to elucidate the underlying molecular mechanisms involved in pathogenesis of pulmonary hypertension.
Role: co-Investigator

Chancellor’s Undergraduate Research Award, 9/1/2012-5/30/2013.
Role: Mentor; Mentee: Iryna Shak

Faculty Mentor Research Funds, 9/1/2012-5/30/2013.
Role: Principle Investigator

Advancing Newborn Medicine Grant Program for Fellows in Neonatology sponsored by Ikaria® , $10,000, 1/1/2011-6/30/2012.
"Role of Adenosine Monophosphate Protein Kinase (AMPK) in Pulmonary Arterial Hypertension."
The goal of this project is to determine the role of AMPK in hypoxia mediated pulmonary arterial hypertension and molecular mechanism participated in the pulmonary arterial smooth muscle cell survival during hypoxia.
Role: Mentor; Mentee: Joyce C. F. Ibe, MD

University of Illinois Cancer Center Pilot Subsidy Program, 2011-2012.
Role: Principle Investigator

Pending research support

1R03CA171700-01, Pending, 04/01/2013-03/31/2015.
"Loss of Cell Polarity Complex Proteins as a Novel Lung Cancer Biomarker."
Role: Principle Investigator

Completed research support

Kabbes Fund Undergraduate Research Award, 1/1/2011-5/30/2011.
"The Role of Protein Kinase A in the Regulation of Epithelial-Mesenchymal Transition in Lung Cancer Cells."
The goal of this project is to determine the role of PKA in hypoxia-mediated epithelial mesenchymal transition and its implication in lung cancer metastasis. 
Role: Mentor; Mentee: Dooniya Shaikh

UIC Center for Clinical and Translational Science (UL1RR029879) supplemental funding, 2010-2011. 
Role: Principle Investigator

UIC faculty scholar fund, 5/1/2009-4/30/2010.
Role: Principle Investigator

Parker B. Francis Research Award, 7/1/2006-6/30/2009.
"Role of von Hippel-Lindau protein on hypoxia-mediated degradation of alveolar epithelial Na,K-ATPase."
The goal of this project is to determine the HIF-independent function of von Hippel Lindau protein in degradation of plasma membrane Na,K-ATPase during hypoxia and its implication in pulmonary edema clearance.
Role: Principle Investigator (Mentor: Dr. Jacob I. Sznajder)

American Heart Association Pre-doctoral Fellowship 0215137B, 7/1/2002-6/30/2004.
"Regulation and Function of Ser/Thr Protein Phosphatases in Response to Oxidative Stress."
The goal of this project was to determine the mechanism of Ser/Thr protein phosphatase 5 upregulation by HIF1 during hypoxia and evaluate the function of PP5 in cell apoptosis induced by ROS during ischemia-reperfusion.
Role: Principle Investigator (Mentor: Dr. Richard E. Honkanen)

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