This Clinical Investigator Development Award is designed to provide support for James L. Lewis, M.D. to allow for the development of an academic career in basic hypertension research. Dr. Lewis is a board-certified Nephrologist who has received his initial research training in the laboratory of David G. Warnock, M.D. His research interests include genetic mechanisms of hypertension, and population genetics. Because of the applicant's prior research experience, the research training plan of this proposal is designed to provide the applicant with a period of intensive supervised research activity under the guidance of sponsor, Dr. Warnock, and co-sponsor, Rodney C. P. Go, Ph.D. of the Department of Epidemiology, School of Public Health. The University of Alabama at Birmingham Medical Center which provides the setting for this program, is a major biomedical research institution. The Department of Medicine's extramural research support is the largest in the school and is in the top 10 Departments of Medicine in the-U.S. in NIH-funding. The Nephrology Research and Training Center (NRTC) employs 14 full-time faculty members, 7 of whom are engaged primarily in basic science research activities. Dr. Warnock, the Director of the Division of Nephrology and the NRTC, is an established scientist with an interest in models of salt-sensitive hypertension. He will direct the research aspect of this program. Dr. Go is an established researcher in the field of population genetics and will assist with the research training activities as well as provide expert advice on experimental design and analysis-of data. The research plan of this proposal is designed to study the genetic causes of hypertension in an inbred rat model. We will breed Dahl/Rapp salt-sensitive (S) and salt-resistant (R) rats to generate Fl and F2 populations. F2 rats will each undergo phenotypic blood pressure determination. A series of polymorphic markers will be identified between S and R using the random amplified polymorphic DNA (RAPD) technique. Those markers which cosegregate with hypertension will then be determined with the, use of bulked segregant analysis. Somatic hybrid cell lines will be created between Dahl/Rapp rat thymocytes and mouse hybridoma cells. The genomic DNA of these cells will be used to create bulked samples which either do or do not contain the rat renin (REN) gene. These bulks will be screened for RAPD with those primers which identify polymorphisms between S and R rats. The resulting chromosome markers will then be used to create a high density map around the REN locus on rat chromosome 13 and to determine which locus is most tightly associated with hypertension. The final stage of this project is the development of congenic strains of Dahl/Rapp rats to determine the physiological contribution of these loci to hypertension in this model. This work relates to human health in that it will provide new insights into the relation between the renin gene and hypertension.
| Lewis, J L; Russell, R J; Warnock, D G (1994) Analysis of the genetic contamination of salt-sensitive Dahl/Rapp rats. Hypertension 24:255-9 |
| Lewis, J L; Serikawa, T; Warnock, D G (1993) Chromosomal localization of angiotensin II type 1 receptor isoforms in the rat. Biochem Biophys Res Commun 194:677-82 |
