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Thomas Jefferson University - Walter J Koch, Ph.D.
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Walter J Koch, Ph.D.
Thomas Jefferson University
Jefferson Medical College
Director of the Center for Translational Medicine
W.W. Smith Professor of Medicine
Vice-Chairman for Research within the Department of Medicine
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Mailing Address
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Center for Translational Medicine
1025 Walnut Street, 4th floor
Philadelphia, Pennsylvania 19107
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Expertise and Research Interests
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The Koch laboratory currently is investigating molecular mechanisms involved in the regulation of signaling through cardiovascular adrenergic receptors (ARs) and the role this plays in heart disease, primarily heart failure (HF). The labs research primarily targets a family of kinases known to regulate ARs and other G protein-coupled receptors (GPCRs) known as the GPCR kinases (GRKs). These GRKs appear to be critically involved in normal and failing heart function and we are manipulating the expression and activity of GRKs in the cardiovascular system. To do this, we utilize novel genetically engineered mouse models and also adenoviral-mediated myocardial gene delivery. Signaling information delineated to be involved in the pathogenesis of heart disease is utilized to design potential novel molecular therapeutic strategies for heart disease. This includes an ultimate goal of the laboratory to develop gene therapy protocols for HF utilizing novel intracoronary delivery techniques. These delivery techniques as well as "proof of concept" testing of molecular targets in the heart are currently being carried out in vivo in both small and large animal models of HF. Currently, a clinical trial is being planned. We also have a clinical/translational program investigating novel blood-borne biomarkers in HF. In addition to HF, programs are ongoing in the laboratory to investigate novel ways to protect the heart against ischemia-induced myocyte apoptosis. Another program in the lab is the investigation of novel non-GPCR roles for the GRKs in cardiovascular cells. Importantly, we have found that one GRK, GRK5, can localize in the nucleus of cardiomyocytes where is can regulate gene transcription involved in pathological cardiac hypertrophy and HF. We continue to pursue new directions involving the role of GRKs in cardiovascular regulation and disease using in vitro and in vivo models.
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Publications
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- Hata JA, Williams ML, Schroder JN, Lima B, Keys JR, Blaxall BC, Petrofski JA, Jakoi A, Milano CA, Koch WJ: Lymphocyte levels of GRK2 (BARK1) mirror changes in the LVAD-supported failing human heart: Lower GRK2 associated with improved beta-adrenergic signaling after mechanical unloading. J Card Fail 12:360-368, 2006.
- Lymperopoulos T, Rengo G, Funakoshi H, Eckhart AD, Koch WJ: Adrenal GRK2 up-regulation mediates sympathetic overdrive in heart failure. Nature Medicine 13:315-323, 2007.
- Pleger ST, Most P, Boucher M, Soltys S, Chuprun JK, Pleger W, Gao E, Rengo G, Remppis A, Katus HA, Eckhart AD, Rabinowitz JE, Koch WJ: Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue. Circulation 115:2506-15, 2007.
- Whalen EJ, Foster MW, Matsumoto A, Ozawa K, Que LG, Violin JD, Benhar M, Keys SR, Koch WJ, Daaka Y, Lefkowitz RJ, Stamler J: Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G protein-coupled receptor kinase 2. Cell 129:511-522, 2007.
- DeGeorge Jr. BR, Gao E, Boucher M, Vinge LE, Martini JS, Raake P, Chuprun JK, Harris DM, Kim GW, Soltys S, Eckhart AD, Koch WJ: Targeted inhibition of myocardial Gi signaling enhances susceptibility to apoptotic cell death in response to stress. Circulation 117:1378-1387, 2008.
- Liggett SB, Cresci S, Kelly RJ, Syed FM, Matkovitch SJ, Hahn HS, Diwan A, Martini JS, Sparks L, Parekh RR, Spertus JA, Koch WJ, Kardia SL Dorn 2nd GW: A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nat Med 14:510-517, 2008.
- Martini JS, Raake P, Vinge LE, DeGeorge B Jr, Chuprun JK, Harris DM, Gao E, Eckhart AD, Pitcher JA, Koch WJ: Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes. Proc Natl Acad Sci USA 105:12457-12462, 2008.
- Raake P, Vinge LE, Gao E, Boucher M, Chem X, Kerkela R, DeGeorge Jr BR, Matkovich S, Houser SR, Most P, Eckhart AD, Dorn II GW, Koch WJ: G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circ Res 103:413-422, 2008.
- Lymperopoulus A, Rengo G, Zincarelli C, Soltys S, Koch WJ: Physiological and pathophysiological adrenal angiotensin II-induced aldosterone production and secretion are beta- arrestin-1 dependent. Proc Natl Acad Sci USA 106:5825-5830, 2009.
- Rengo G, Lymperopoulos A, Zincarelli C, Donniacuo M, Soltys S, Rabinowitz JR, Koch WJ: Myocardial adeno-associated virus serotype-6-betaARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure. Circulation 119:89-98, 2009.
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Individual Expertise profile of
Walter J Koch, Ph.D., Copyright © Walter J Koch, Ph.D..
Last Updated
by Walter Koch, Ph.D. : Wednesday, October 14, 2009 11:39:05 AM
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