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Raj Kishore, PhDAssistant Professor
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Current Research Interests
1 ) To understand molecular mechanisms and signal transduction involved in the inflammatory cytokines (e.g. TNF-alpha)-induced dysfunction of endothelial cells (EC) in cell culture model system and the mechanisms of cytokine regulation on the healing of endothelium in vivo in moue models of carotid artery denudation (equivalent to balloon angioplasty in patients). We have established that locally secreted TNF acts to inhibit endothelial recovery leading to restenosis, partly via inducing cell cycle arrest in ECs (Kishore, Circulation Research 2002, 2003; JCI, 2005),although complete molecular mechanisms and signal transduction pathways involved therein are yet to be deciphered. Understanding of EC gene regulation may potentially help finding target molecules whose modulation can nullify deleterious effects of TNF. Another component of this project involves elucidating trans-factors involved in posttranscriptional (mRNA stability) regulation of TNF by anti-inflammatory cytokine IL-10 (Rajasingh,Kishore, FASEB J, 2006).
2) To understand the molecular and signaling mechanisms governing directed differentiation of mouse embryonic and adult stem cells and oocyte-independent means for the de-differentiation of adult somatic cells to generate stem-like cells and to assess the therapeutic efficacy of these cells towards tissue repair in mouse models of surgically induced myocardial infarction and other ischemic injuries.
3) To study and understand the role of long-term alcohol consumption (chronic alcoholism) on cardiovascular system. Chronic ethanol inhibits cell survival signaling by various mechanisms, including but not limited to the enhanced release of TNF and other pro-inflammatory cytokines. Our studies indicate that in vitro chronic ethanol exposure exerts inhibitory effects on EC proliferation and survival (Luedemann, Kishore, Alco Clin Exp Res, 2005; Rajasingh, Kishore, Endocrinology, 2007). Chronic ethanol not only elevates agonist-induced TNF expression in EC but also exacerbates TNF-mediated EC dysfunction, synergistically. Our current studies are focused toward understanding the biology of ethanol-induced EC dysfunction in ethanol-fed rodent models as wells as towards understanding the underlying molecular mechanisms in cell culture model system.
Rajasingh J, Hamada H, Bord E, Qin G, Mehta S, Silver M, Zhu Y, Goukassian D, Losordo DW, and Kishore R. STAT3-dependent mouse Embryonic Stem Cell Differentiation into Cardiomyocytes: Analysis of Molecular Signaling and Therapeutic Efficacy of Cardiomyocyte Pre-committed mES in a Mouse Model of myocardial Infarction; Circ Res, in press.
Rajasingh J, Bord E, Qin G, Ii M, Silver M, Hamada H, Goukassian D, Zhu Y, Losordo DW, Kishore R. Enhanced Voluntary Alcohol Consumption Following Estrogen Supplementation Negates Estrogen- mediated Vascular Repair in Ovariectomized Mice. Endocrinology; ePub ahead of print May 3’2007.
Rajasingh J, Bord E, Luedemann C, Asai J, Hamada H, Iwakura A, Thorne T, Qin G, Goukassian D, Zhu Y, Losordo DW, Kishore R. IL-10-induced TNF-alpha mRNA Destabilization is Mediated via IL-10 Suppression of p38 MAP Kinase Activation and Inhibition of HuR Expression. FASEB J; 20(12): 2112-4.
Kengo F. Kusano, Roberto Pola, David Goukassian, Young-sup Yoon, William Munger, Cynthia Curry, Toshinori Murayama, Atsuhiko Kawamoto, Atsushi Iwakura, Satoshi Shintani, Masaaki Ii, Tina Thorne, Hideya Takenaka, Ryuichi Aikawa, Patrick von Samson, Tengiz Tkebuchava, Hiromichi Hamada, Ingrid Johnson, Marcy Silver, Elizabeth Eaton, Hong Ma, Lindsay Heyd, Marianne Kearney, Jeffery A. Porter, Raj Kishore and Douglas W. Losordo. Sonic Hedgehog Gene Therapy in Myocardial Ischemia: Tissue Preservation and Regeneration via Transient Reconstitution of Embryonic Signaling. Nature Med, 11(11):1197-204, 2005.
Kishore R, Qin G, Luedemann C, Bord E, Hanley A, Silver M, Gavin M, Goukassian D, Losordo DW. The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-alpha-induced transcriptional repression of cyclin A. J Clin. Invest. 115: 1785-96, 2005
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View Publications by Raj Kishore listed in the National Library of Medicine (PubMed). |
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