PHA/NHLBI K08/K23 Award Winner 2010

Stephen Y. Chan, MDStephen Y. Chan, MD

Brigham and Women’s Hospital/Harvard Medical School
"Functions of Hypoxia-Induced MicroRNA-210 in Pulmonary Vascular Endothelium"
NHLBI Mentored Clinical Scientist Development Award (K08)
August 1, 2010 - July 31, 2015

Summary of Research Project:

"Functions of the Hypoxia-Induced MicroRNA-210 in Pulmonary Vascular Endothelium"

Our research focuses on the molecular mechanisms by which the pulmonary artery (and the pulmonary arterial endothelial cell or PAEC in particular) responds to injury, such as inadequate oxygen availability (“hypoxia”). It is widely appreciated that, in response to hypoxia, the PAEC undergoes metabolic adaptations important in the development of pulmonary hypertension (PH), a complex disease state characterized by increasing pulmonary arterial pressures. If untreated, PH can lead to heart failure, volume overload, and death. However, further details of the molecular processes by which hypoxia causes PH remain enigmatic.

We have hypothesized that non-canonical, non-protein coding genes may control these key events in disease progression. Endogenous microRNA molecules (miRNA) are such recently described non-canonical regulatory factors. They are small, non-protein coding RNA molecules that are largely conserved through evolution. It is estimated that greater than thirty percent of all human genes are regulated by miRNA in some context, but the functions of only a few specific miRNA molecules have been characterized to date.

In the nineteenth century, Louis Pasteur first described a fundamental cellular response to hypoxia, resulting from a metabolic shift from mitochondrial respiration to glycolysis. Over the past two years, we have identified microRNA-210 (miR-210) as an essential regulator of the metabolic processes that govern this “Pasteur effect,” via repression of the iron-sulfur cluster assembly proteins ISCU1/2 and consequent perturbation of cellular respiration during hypoxia. These results have established an entirely novel mechanism that clarifies our fundamental understanding of the cellular adaptation to hypoxia.

In our proposed studies, we plan to determine whether such control of cellular metabolism by miR-210 promotes the development of PH via disrupting mitochondrial function and altering levels of toxic reactive oxygen species and nitric oxide. Using a combination of bioinformatics, cell-culture based assays, and unique mouse and rat models of PH, this proposal will provide a comprehensive description of the miR-210/ISCU1/2 regulatory axis in the pulmonary arteries of living mammals. In doing so, this work is expected to improve our fundamental understanding of pulmonary vascular injury and may offer novel possibilities for diagnosis and treatment of PH to benefit this growing and historically long-suffering population of patients.

Curriculum Vitae

Current Position

Instructor of Medicine, Harvard Medical School; Associate Physician, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital

Education

  • 09/91-06/95 Bachelor of Science, Biology (Minor in Chemistry), Massachusetts Institute of Technology, Cambridge, MA
  • 09/95-06/03 MD, PhD, (Medical Scientist Training Program) Medicine and Biomedical Sciences,
    University of California, San Francisco, San Francisco, CA

Post-Doctoral Training

  • 07/03-06/05 Intern/Resident, Internal Medicine, Brigham and Women’s Hospital, Boston, MA
  • 07/05-06/09 Clinical and Research Fellow in Medicine, Cardiology, Massachusetts General Hospital, Boston, MA
  • 07/05-06/09 Research Fellow in Medicine, Cardiology, Harvard Medical School, Boston, MA

Positions and Employment

Academic Appointments/Hospital Appointments:

  • 6/2003-6/2005 Internship and Residency in Internal Medicine
    Department of Medicine, Brigham and Women’s Hospital (BWH)
  • 7/2005-6/2009 Clinical and Research Fellow in Medicine
    Harvard Medical School
    Division of Cardiology, Department of Medicine, Massachusetts General Hospital (MGH)
  • 7/2009-6/2010 Instructor of Medicine
    Harvard Medical School
    Graduate Assistant in Medicine
    Massachusetts General Hospital (MGH)
  • 7/2010-present Instructor of Medicine
    Harvard Medical School
    Associate Physician
    Brigham and Women’s Hospital (BWH)

Other Experience and Professional Memberships

Licensure and Certification:

  • 6/2007 - 6/2009 Full License, state of Massachusetts (Internal Medicine)
  • 10/2007-10/2017 American Board of Internal Medicine, Internal Medicine
  • 10/2009-present American Board of Internal Medicine, Cardiovascular Medicine, Board Eligible

Professional Societies:

  • 2003-present Massachusetts Medical Society, Member
  • 2005-present American College of Cardiology, Member
  • 2006-present American Heart Association, Member

Honors

  • 1991 United States Presidential Scholar
  • 1991 Tandy Technology Scholar
  • 1995 Sigma Xi-The Scientific Research Society, MIT
  • 1995 Society of Phi Beta Kappa, MIT
  • 1995 Recipient of NIH-sponsored Medical Scientist Training Program (MSTP) grant, UCSF
  • 1997 Letter of Distinction in Pathology, UCSF
  • 1999 Leslie Bennett Memorial Award for Excellence in Teaching as graduate teaching assistant for Medicine I course IDS 100 (Histology), UCSF
  • 2000 The J. David Gladstone Institutes Prize for Scientific Excellence, Joint Scientific Retreat, UCSF
  • 2000 Chancellor's Graduate Research Fellowship, UCSF
  • 2000 Travel Award for the Symposium on Marburg and Ebola Viruses, Marburg, Germany
  • 2000 The Trefethen Family Biomedical Research Award, UCSF
  • 2001 The Raymond W. Sarber Graduate Student Award sponsored by the American Society for Microbiology
  • 2001 The Harold M. Weintraub Graduate Student Award sponsored by the Fred Hutchinson Cancer Research Center, Seattle, WA
  • 2001 Phi Beta Kappa of Northern California Graduate Student Award
  • 2003 Alpha Omega Alpha Medical Honor Society, UCSF
  • 2006 The William A. Schreyer Cardiology Fellow Award, MGH
  • 2009 Poster of Distinction, 62nd Annual Meeting of the MGH Scientific Advisory Committee
  • 2009 Herman K. Gold Young Investigator's Award in Molecular and Cellular Cardiology sponsored by the American College of Cardiology
  • 2009 First Place, Fellows Basic Science, Northwestern Cardiovascular Young Investigators’ Forum
  • 2009 Finalist, Louis N. and Arnold M. Katz Basic Science Research Prize for Young Investigators, American Heart Association
  • 2010 Winner, Lerner Research Symposium, BWH (Cardiovascular Division)

Editorial Activities

  • Ad hoc Reviewer: Circulation, Circulation: Cardiovascular Genetics, American Journal of Respiratory Cell and Molecular Biology

Honor Societies

  • 06/95 Sigma Xi-The Scientific Research Society, Massachusetts Institute of Technology
  • 06/95 Society of Phi Beta Kappa, Massachusetts Institute of Technology
  • 06/03 Alpha Omega Alpha Medical Honor Society, University of California, San Francisco

Invited Scientific Presentations

  • 04/09 Regulation and Function of Hypoxia-Inducible MicroRNA in Human Pulmonary Arterial Endothelial Cells
    Annual Meeting of the American College of Cardiology, Orlando, FL, USA
  • 09/09 MicroRNA-210 Controls Mitochondrial Metabolism and Hypoxic Adaptation in Pulmonary Vascular Endothelium
    Northwestern Cardiovascular Young Investigators’ Forum, Chicago, IL, USA
  • 11/09 MicroRNA-210 Controls Metabolic Adaptation during Hypoxia in Pulmonary Vascular Endothelium
    Scientific Sessions 2009, American Heart Association, Orlando, FL, USA
  • 3/11 MicroRNA-210 Controls Mitochondrial Function in Ischemic Vasculature
    75th Annual Scientific Meeting of the Japanese Circulation Society, Yokohama, Japan

Research Support

Ongoing Research Support:

  1. National Institutes of Health, National Heart, Lung, and Blood Institute (K08 Mentored Clinical Scientist Development Award) 4/1/10-3/30/11
  2. William Randolph Hearst Fund for Pre- and Peri-natal Research, 7/1/10-6/30/11
  3. Pulmonary Hypertension Association (Pulmonary Hypertension Association and the National Heart, Lung, and Blood Institute Jointly Sponsored Mentored Clinical Scientist Development Award), 8/1/10-7/31/15

Completed Research Support:

  1. American Heart Association Founders Affiliate Postdoctoral Grant, 7/1/08-6/30/10

Publications

Peer-Reviewed Articles:

  1. Marcinek A, Platz MS, Chan SY, Floresca K, Rajagopalan K, Golinski M, Watt DS. Unusually long lifetimes of the singlet nitrenes derived from 4-azido-2,3,5,6-tetrafluorobenzamides. Journal of Physical Chemistry. 1994; 98 (2): 412-419. [DOI: 10.1021/j100053a012]
  2. Chan SY, Speck RF, Power C, Gaffen SL, Chesebro B, Goldsmith MA. V3 recombinants indicate a central role for CCR5 as a coreceptor in tissue infection by human immunodeficiency virus type 1. Journal of Virology. 1999; 73 (3): 2350-2358. [PMID 9971818]
  3. Speck RF, Esser U, Penn ML, Eckstein DA, Pulliam L, Chan SY, Goldsmith MA. A trans-receptor mechanism for infection of CD4-negative cells by human immunodeficiency virus type 1. Current Biology. 1999; 9 (10): 547-550. [PMID 10339429]
  4. Schramm B, Penn ML, Speck RF, Chan SY, De Clercq E, Schols D, Connor RI, Goldsmith MA. Viral entry through CXCR4 is a pathogenic factor and therapeutic target in human immunodeficiency virus type 1 disease. Journal of Virology. 2000; 74 (1): 184-192. [PMID 10590105]
  5. Chan SY, Speck RF, Ma MC, Goldsmith MA. Distinct mechanisms of entry by envelope glycoproteins of Marburg and Ebola (Zaire) viruses. Journal of Virology. 2000; 74 (10): 4933-4937. [PMID 10775638]
  6. Chan SY, Ma MC, Goldsmith MA. Differential induction of cellular detachment by envelope glycoproteins of Marburg and Ebola (Zaire) viruses. Journal of General Virology. 2000; 81(Pt 9): 2155-2159. [PMID 10950971]
  7. Chan SY, Empig CJ, Welte FJ, Speck RF, Schmaljohn A, Kreisberg JF, Goldsmith MA. Folate receptor-a is a cofactor for cellular entry by Marburg and Ebola viruses. Cell. 2001; 106 (1): 117-126. [PMID 11461707]
  8. Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metabolism. 2009; 10 (4); 273 – 284 [DOI:10.1016/j.cmet.2009.08.015].

Review Articles and Book Chapters:

  1. Chan SY and Goldsmith MA. Molecular Mechanisms of Filovirus Entry. In: Klenk, H, Feldmann, H, editors. Ebola and Marburg Viruses: Molecular and Cellular Biology. Norfolk, UK: Horizon Scientific Press; 2004. p. 91-135.
  2. Chan SY and Loscalzo J. Pathogenic Mechanisms of Pulmonary Arterial Hypertension. Journal of Molecular and Cellular Cardiology. 2008; 44 (1):14-30. [PMID 17950310].
  3. Chan SY and Loscalzo J. MicroRNA-210: A Unique and Pleiotropic Hypoxamir. Cell Cycle. 2010; 9 (6).
  4. Chan SY and Loscalzo J. Endothelial Regulation of Pulmonary Vascular Tone. In: Yuan JX, Garcia J, Hales CA, Stuart R, Archer SL, West JB, editors. Textbook of Pulmonary Vascular Disease. 2010. In Press.
  5. Chan SY and Loscalzo J. Pulmonary Vascular Disease Related to Hemodynamic Stress in the Pulmonary Circulation. In: McMurty IF, editor. Comprehensive Physiology. 2010. In Press.

 

 

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