A five year program of didactic training and research is proposed to examine the role of gene regulation in renal physiologic adaptive mechanisms. During phase one of the program I will undertake formal instruction in molecular biology and genetics while studying the regulation of renin gene expression. During phase two I will use the concepts and techniques developed in the first phase to study the genetic control of renal transport processes. The phase one didactic program will be designed around the core curriculum of the graduate program in Biochemistry and Biophysics and UCSF in conjunction with the research conferences in the Metabolic Research Unit and division of Nephrology. The research during phase one will be directed at localizing and characterizing the enhancer and promoter elements which confer tissue-specific expression to the renin gene. A cell lines has been found which expresses the renin gene only in certain media. This property will be exploited to localize the tissue-specific gene regulatory regions by use of DNase I hypersensitivity, """"""""gel shift"""""""" and """"""""footprint"""""""" assays. Candidate regulatory sites will be tested for enhancer, promoter, or repressor activity by assessing their effect on transcription from a homologous or heterologous promoter in a recombinant construction using transfer. The trans-acting factors which act on these sites will then be identified and characterized. The Na+/N+ antiporter responds to a number of stimuli (e.g., acidosis) in a manner consistent with an increase in its biosynthesis. The specific goal in phase two of the program will be to design and implement an independent research project directed at determining whether transcritpional control is exerted in the response of the antiporter to these stimuli, and if so, to determine the underlying mechanisms. This program of didactic training and research will provide the basis for subsequent study of not only the antiporter but also potentially of the gene regulatory events implicated in the control of other transport systems.
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