Faculty Profile: Chi-Ming Hai, Ph.D., Johns Hopkins University, 1984

Chi-Ming Hai
Chi-Ming Hai, Ph.D., Johns Hopkins University, 1984
Professor
Molecular Pharmacology, Physiology & Biotechnology
Work: +1 401-863-3288
Vascular and airway smooth muscle cell physiology, cell biology, and systems biology – in relation to atherosclerosis, vasoconstriction, and asthma - are the foci of our research. We presently pursue the following research projects.
1. Nicotine-Induced Vascular Smooth Muscle Invasion.
2. Systems Biology of Hemoglobin-Based Oxygen Carrier (HBOC)-Induced Vasoconstriction.
3. Mechanosensitive Modulation of Cytoskeletal Remodeling in Airway Smooth Muscle.

Biography

Chi-Ming Hai, Ph.D. graduated from the University of Toronto with a B.S. in Physiology in 1978. He continued his studies in Physiology at the School of Medicine at the University of Ottawa, receiving his M.S. degree in 1980. He then proceeded to the School of Medicine at Johns Hopkins University in Maryland where he graduated with his Ph.D. in Physiology in 1984. Dr. Hai has been teaching at Brown University since 1988.

Institutions

Bu

Research Description

Vascular and airway smooth muscle cell physiology, cell biology, and systems biology – in relation to atherosclerosis, vasoconstriction, and asthma - are the foci of our research. We presently pursue the following research projects.

Nicotine-Induced Vascular Smooth Muscle Invasion.
Cigarette smoking is a significant risk factor for atherosclerosis, which involves the invasion of vascular smooth muscle cells (VSMCs) from the media to intima. A hallmark of many invasive cells is actin cytoskeletal remodeling in the form of podosomes, accompanied by extracellular matrix (ECM) degradation. A7r5 VSMCs form podosomes in response to PKC activation. We found that cigarette smoke extract, nicotine, and the cholinergic agonist, carbachol, were similarly effective in inducing the formation of podosome rosettes in A7r5 VSMCs. α-Bungarotoxin and atropine experiments confirmed the involvement of nicotinic acetylcholine receptors (nAChRs). Western blotting and immunofluorescence experiments revealed the aggregation of nAChRs at podosome rosettes. Cycloheximide experiments and media exchange experiments suggested that autocrine factor(s) and intracellular phenotypic modulation are putative mechanisms. In situ zymography experiments indicated that, in response to PKC activation, nicotine-treated cells degraded ECM near podosome rosettes, and possibly endocytose ECM fragments to intracellular compartments. Invasion assay of human aortic smooth muscle cells indicated that nicotine and PKC activation individually and synergistically enhanced cell invasion through ECM. We hypothesize that nicotine enhances the ability of VSMCs to degrade and invade ECM. nAChR activation, actin cytoskeletal remodeling and phenotypic modulation are possible mechanisms.

Systems Biology of Hemoglobin-Based Oxygen Carrier (HBOC)-Induced Vasoconstriction.
HBOCs are designed to carry oxygen to organ systems via the circulation. Unfortunately, HBOCs also scavenge nitric oxide (NO) - an important relaxing factor released by endothelial cells, and thereby reduces the availability of NO to vascular smooth muscle cells, disrupts NO-mediated cascade of signaling pathways in vascular smooth muscle cells, and causes vasoconstriction. Furthermore, in the presence of oxygen, HBOCs can undergo autoxidation with the generation of reactive oxygen species (ROS), which can lead to endothelial barrier dysfunction. HBOCs can then permeate through the leaky endothelial cell-cell junctions to the interstitial space near vascular smooth muscle cells, thereby further reducing the bioavailability of NO to vascular smooth muscle cells and causes vasoconstriction. The use of a single drug for attenuating HBOC-induced vasoconstriction has been tried with limited success. Since HBOC causes disruptions at multiple levels of organization in the vascular system, a systems approach is helpful to explore avenues to counteract the effects of HBOC at multiple levels by targeting multiple sites in the system. A multi-target approach is especially appropriate for HBOC-induced vasoconstriction, because HBOC disrupts the cascade of amplification by NO-cGMP signaling and protein phosphorylation, ultimately resulting in vasoconstriction. Identifying targets and doses for developing a multi-target combination HBOC regimen for oxygen therapeutics requires a detailed understanding of the systems biology and phenotypic heterogeneity of the vascular system at multiple layers of organization, which can be accomplished by successive iterations between experimental studies and mathematical modeling at multiple levels of vascular systems and organ systems.

Mechanosensitive Modulation of Cytoskeletal Remodeling in Airway Smooth Muscle.
Airway smooth muscle (ASM) hyperresponsiveness is an important problem in asthma. Recent studies indicated that bronchodilators are relatively ineffective in dilating closed airways in asthmatics, suggesting that mechanisms other than actomyosin crossbridge-based contraction may mediate airway closing in asthmatics. We have postulated that agonist-stimulated ASM functions as a hybrid biomaterial, capable of switching between functioning as a cytoskeleton-based viscoelastic body at short length and as a crossbridge-based contractile cell at long length. Accordingly, we hypothesize that phosphatidylinositol 4,5-bisphosphate (PIP2) functions as a length-dependent switch in mechanosensitive modulation of cytoskeletal recruitment and crossbridge cycling in agonist-stimulated ASM. PIP2 breakdown catalyzed by PLC is a major signal transduction mechanism for generating inositol trisphosphate and diacylglycerol for activating crossbridge cycling. In contrast, the PIP2 molecule itself also functions as an important signaling molecule, because PIP2 can recruit cytoplasmic proteins having phosphoinositide recognition domains to the cell membrane. Agonist-stimulated PIP2 breakdown is length-dependent in ASM; therefore, PIP2 content should be up-regulated at short muscle length and down-regulated at long muscle length. This hypothesis predicts that PIP2 content-dependent cytoskeletal recruitment and PIP2 breakdown-dependent crossbridge cycling should change in opposite directions as a function of muscle length. This prediction challenges the current paradigm that cytoskeletal recruitment and crossbridge cycling change in the same direction during contraction-relaxation cycles in ASM.

Grants and Awards

2006 Dean's Teaching Excellence Award, Brown Medical School

2004 Dean's Teaching Excellence Award, Brown Medical School

2003 Exemplary Online Course Using WebCT Recognition for Biomed 117, Brown University

1983 Certificate of Merit for Young Investigators, Johns Hopkins University

Affiliations

American Society for Cell Biologists
Biophysical Society
Invadosome Consortium

Funded Research

2008-2009 Principal Investigator, NIH R56 Research Grant Award (HL52714)

2007-2008 Principal Investigator, Naval Medical Research Center (N00189-07-C-Z086)

1996-2005 Principal Investigator, NIH R01 Research Grant Award (HL52714)

1991-1994 Principal Investigator, American Heart Association, National Center, Grant-in-Aud Award (91008460)

1989-1992 Principal Investigator, National Science Foundation Research Grant Award (8902438)

Teaching Experience

2008-Present Course Leader Biomed 116 Exercise Physiology
2007-Present Course Leader Biomed 80 Principles of Physiology
1991-2007 Lecturer Biomed 80 Principles of Physiology
1991-92 Course Leader Biomed 80 Principles of Physiology
1994-95 Course Leader Biomed 110 Cell Physiology and Biophysics
2003-04 Lecturer Biomed 113 Cell Structure and Movement
1989-06 Course Leader Biomed 117 Mammalian Physiology
1989-90 Lecturer Biomed 118 Comparative Physiology
1992-93 Seminar Speaker Biomed 209 Special Topics in Respiratory Physiology
2006 Lecturer Biomed 217 Molecular Pharmacology & Physiology

Independent Studies (Since Tenure in 1994)
1994-2008 ~41 Students (28 received honors, and 3 received prizes)
2005 David Beck, Recipient of Morris L. Povar Prize in Physiology or
Zoology
1999 Jennifer Zander, Recipient of Morris L. Povar Prize in Physiology or Zoology
1995 Edwin Cadet, Recipient of Morris L. Povar Prize in Physiology or Zoology

Ph.D. Graduates Directed
2007 Zhizhan Gu, Post-doctoral Fellow, Harvard Medical School
2006 Hak Rim Kim, Post-doctoral Fellow, Boston University
2000 Steven An, Assistant Professor, Johns Hopkins School of Public Health

Courses Taught

  • Cell Physiology and Biophysics (BIOL1100)
  • Cell Structure and Movement (BIOL1130)
  • Comparative Animal Physiology (BIOL1180)
  • Mammalian Physiology (BIOL1170)
  • Molecular Pharmacology and Physiology (BIOL2170)
  • Principles of Exercise Physiology (BIOL1160)
  • Principles of Physiology (BIOL0800)
  • Special Topics in Respiratory Physiology (BIOL2090)

Selected Publications

  • Gu, Z., V. Fonseca, and C.-M. Hai. Nicotinic acetylcholine receptor mediates nicotine-induced actin cytoskeletal remodeling and extracellular matrix degradation by vascular smooth muscle cells. Vascular Pharmacology, 2012 (doi: 10.1016/j.vph.2012.08.003). (2012)
  • Hai, C.M. Systems biology of HBOC-induced vasoconstriction. Curr. Drug. Discovery Technol. 9: 204-211, 2012 (2012)
  • Aron, A.W., E.E. Macksoud, R.V. Iozzo, C.-M. Hai, and B.E. Lechner. Uterine dysfunction in biglycan and decorin deficient mice leads to dystocia during parturition. PLoS ONE 7: e29627, 2012 (2012)
  • Kim, H.R., K. Liu, T.J. Roberts, and C.-M. Hai. Length-dependent modulation of cytoskeletal remodeling and mechanical energetics in airway smooth muscle. Am. J. Respir. Cell Mol. Biol. 44: 888-897, 2011 (2011)
  • Fonseca, V., J. Avizinis, P. Moon-Massat, D. Freilich, H.W. Kim, and C.M. Hai. Differential sensitivities of pulmonary and coronary arteries to hemoglobin-based oxygen carriers and nitrovasodilators: Study in a bovine ex vivo model of vascular strips. Vasc. Pharmacol. 52: 215-223, 2010 (2010)
  • Kim, H.-W., C.-M. Hai, and G. Greenburg. Acellular hemoglobin-based oxygen carrier induced vasoconstriction and hypertension: a brief review of potential pharmacologic remedies. Artificial Blood 17: 147-159, 2009 (2009)
  • Hai, C.-M. Mechanistic systems biology of inflammatory expression in airway smooth muscle as tool for asthma drug development. Curr. Drug. Discovery Technol., 2008 (Accepted for Publication) (2008)
  • Hai, C.-M. Caldesmon as a therapeutic target for proliferative vascular diseases. Mini-Reviews in Medicinal Chemistry 8: 1209-1213, 2008 (2008)
  • Hai, C.-M. Airway smooth muscle cell as therapeutic target of inflammation. Curr. Med. Chem. 14: 67-76, 2007 (2007)
  • Gu, Z., J. Kordowska, G.L. Williams, C.-L.A. Wang, and C.-M. Hai. Erk1/2 MAPK and caldesmon differentially regulate podosome dynamics in A7r5 vascular smooth muscle cells. Exp. Cell Res. 313: 849-866, 2007 (2007)
  • Kanefsky, J., M. Lenburg, and C.-M. Hai. Cholinergic receptor and cyclic stretch-mediated inflammatory gene expression in intact ASM. Am. J. Respir. Cell Mol. Biol. 34: 417-425, 2006 (2006)
  • Hai, C.-M. and Z. Gu. Caldesmon phosphorylation in actin cytoskeletal remodeling. Eur. J. Cell Biol. 85: 305-309, 2006. (2006)
  • Kim, H.R. and C.-M. Hai. Mechanisms of mechanical strain memory in airway smooth muscle. Can. J. Physiol. Pharmacol. 83: 811-815, 2005 (2005)
  • Hai, C.-M. and H.R. Kim. An expanded latch-bridge model of protein kinase C-mediated smooth muscle contraction. J. Appl. Physiol. 98:1356-1365, 2005 (2005)
  • Lu, Q., E.O. Harrington, C.-M. Hai, J. Newton, M. Garber, T. Hirase, and S. Rounds. Isoprenylcysteine carboxyl methyltransferase modulates endothelial monolayer permeability. Involvement of RhoA carboxyl methylation. Circ. Res., 94: 306-315, 2004. (2004)
  • Kim, H.R., M. Hoque, and C.-M. Hai. Cholinergic receptor-mediated differential cytoskeletal recruitment of actin- and integrin-binding proteins in intact airway smooth muscle. Am. J. Physiol.: Cell Physiol. 287:.C1375-C1383, 2004 (2004)
  • Wahl, M. and C.-M. Hai. Sinusoidal length oscillation and receptor-mediated mRNA expression of myosin isoforms and alpha-SM actin in airway smooth muscle. Am. J. Physiol. Cell Physiol. 287: C1697-C1708, 2004 (2004)
  • Bai, T.R. et al. On the terminology for describing the length-force relationship and its changes in airway smooth muscle. J. Appl. Physiol. 97: 2029-2034, 2004. (2004)
  • Hai, C.-M., G. Sadowska, L. Francois, and B.S. Stonestreet. Maternal Dexamethasone Treatment Modulates Myosin Isoform Expression and Contractile Dynamics in Fetal Carotid Arteries. Am. J. Physiol. Heart Circ. Physiol. 283: H1743-H1749, 2002. (2002)
  • Hai, C.-M., P. Hahne, E.O Harrington, and M. Gimona. Conventional PKC mediates phorbol dibutyrate-induced cytoskeletal remodeling in A7r5 smooth muscle cells. Experimental Cell Research, 280:64-74, 2002. (2002)
  • Silberstein, J. and C.-M. Hai. Dynamics of length-force relations in airway smooth muscle. Respiratory Physiology & Neurobiology 132: 205-221, 2002. (2002)
  • Chan, W.L., J. Silberstein, and C.-M. Hai. Mechanical strain memory in airway smooth muscle. Am. J. Physiol. Cell Physiol. 278: C895-C904, 2000. (2000)
  • An, S.S. and C.-M. Hai. Mechanical signals and mechanosensitive modulation of intracellular [Ca2+] in smooth muscle. Am. J. Physiol. Cell Physiol. 279: C1375-C1384, 2000. (2000)
  • Hai, C.-M. Mechanosensitive modulation of receptor-mediated crossbridge activation and cytoskeletal organization in airway smooth muscle. Arch. Pharmacal Res. 23: 535-547, 2000. (2000)
  • An, S.S. and C.-M. Hai. Mechanical Strain Modulates Maximal Phosphatidylinositol Turnover in Airway Smooth Muscle. Am. J. Physiol 277 (Lung Cell. Mol. Physiol. 21): L968-L974, 1999. (1999)
  • Wong, C.T. and C.-M. Hai. Mucosal modulation of agonist-induced myosin phosphorylation and contraction in airway smooth muscle. Respiration Physiology 115: 103-111, 1999. (1999)
  • Youn, T., S.A. Kim, and C.-M. Hai. Length-dependent modulation of smooth muscle activation: effects of agonist, cytochalasin, and temperature. Am. J. Physiol. 274 (Cell Physiol. 43): C1601-1607, 1998. (1998)
  • Tseng, S., R. Kim, T. Kim, K.G. Morgan, and C.-M. Hai. F-actin disruption attenuates agonist-induced [Ca2+], myosin phosphorylation, and force in smooth muscle. Am. J. Physiol. 272 (Cell Physiol. 41): C1960-C1967, 1997. (1997)
  • Szeto, B. and C.-M. Hai. Length-dependent modulation of myosin phosphorylation and contractile force in coronary arterial smooth muscle. Arch. Biochem. Biophys. 329: 241-248, 1996. (1996)
  • Yoo, J., R. Ellis, K.G. Morgan, and C.-M. Hai. Mechanosensitive modulation of myosin phosphorylation and phosphatidylinositol turnover in smooth muscle. Am. J. Physiol. 267 (Cell Physiol. 36): C1657-C1665, 1994. (1994)