Assistant Professor of Medicine
570 S. Preston St.
Donald Baxter Bldg., Rm. 119C
Louisville, KY 40202
Phone: 502-852-2459
Fax: 502-852-2494
E-mail: dgroko01@louisville.edu

Research Interests

Our lab studies the molecular, cellular, and physiologic function of three a1-adrenergic receptor (AR) subtypes present in the cardiovascular system. Activation of these subtypes by catecholamines protects, or preconditions, the heart from ischemia-induced damage and dysfunction, increases cardiac and smooth muscle contractility important for blood pressure regulation, and increases protein synthesis in vascular and cardiac muscle helping the cardiovascular system adapt to stress. Recently, we have created and used a1-AR subtype knockout mice to study differences in a1-AR subtype signaling. In these studies we have found that each subtype can activate distinct and different signaling pathways. The main focus in our lab is to determine how each a1-AR subtype couples to and activates distinct signaling pathways and whether the subtypes mediate distinct function. We use proteomic and molecular biology approaches to identify receptor domains that are important for interacting with signaling proteins that impart signaling specificity and to identify novel signaling proteins that might interact with one of the subtypes and can account for differences in signaling. a1-AR subtype-specific activation and signaling is correlated with preconditioning against myocardial stunning and infarct and blood pressure regulation using in vivo and in vitro mouse models. Changes in the global gene expression profile associated with the late phase of preconditioning are studied using DNA microarrays. This approach allows us to look for known genes that have not been associated with preconditioning and to identify novel unknown genes that may participate in this phenomenon. Our research focuses on all aspects of a1-AR receptor biology allowing us to understand the functional consequences of the distinct subtypes.

Publications

1. Rokosh, D.G., A.F.R. Stewart, K.C. Chang, B.B. Bailey. J.S. Karliner, S.A. Camacho, C.S. Long, and P.C. Simpson, 1996, a1-Adrenergic receptor subtype mRNAs are differentially regulated by a1-adrenergic and other hypertropic stimuli in cardiac myocytes in culture and in vivo: repression of a1B and a1D but induction of a1C, J. Biol. Chem. 271: 5839-5843.
2. Nakamura, A., D.G. Rokosh, M. Paccanaro, R.R. Yee, P.C. Simpson, W. Grossman, and E. Foster, 2001, LV systolic performance improves with development of hypertrophy after transverse aortic constriction in mice. Am J Physiol Heart Circ Physiol. 281(3):H1104-H1112.
3. Rokosh, D.G. and P.C. Simpson, 2002, Knockout of the a1A/C-adrenergic receptor subtype: the a1A/C is expressed in resistance arteries and is required to maintain arterial blood pressure. Proc. Natl. Acad. Sci. USA. 99 (14):9474-9479.
4. McCloskey, D.T., D. G. Rokosh, T.D. O'Connell, E.C. Keung, P.C. Simpson, and A.J. Baker, 2002, a1-Adrenoceptor subtypes mediate negative inotropy in myocardium from a1A/C -knockout and wild type mice. J. Mol. Cell. Cardiol. 34:1007-1017
5. O'Connell, T.D., S. Ishizaka, A. Nakamura, P.M. Swigart, M.C. Rodrigo, G.L. Simpson, S. Cottechia, D.G. Rokosh, W. Grossman, E. Foster, and P.C. Simpson, 2003, The a1A/C- and a1B-adrenergic receptors are required for physiological cardiac hypertrophy in the double knockout mouse. J. Clin. Invest. 111:1783-1791.