Program Director/Principal Investigator (Last, First, Middle): Sigmund, Curt D.PROJECT SUMMARY (See instnjctions):The renin-angiotensin system is a major regulator of blood pressure and electrolyte balance in animals andhumans and has been implicated in the genetic basis of essential hypertension. Renin is the rate limitingenzyme cascade and its synthesis is highly regulated at both the transcriptional, post-transcriptional andsecretory level. Our efforts ofthe past 15 years have lead to significant advances in our understanding ofthe transcriptional mechanisms regulating this important gene and have begun coupling transcription tophysiology. With the development of new innovative technologies for interrogation of individual genes andproteins in both cells and whole animals, we are now poised for the first time to make important discoverieslinking transcriptional events to specific physiological responses and pathways. Studies in the l/IERITEXTENSION period will continue to focus on the overall hypothesis: The enhancers found upstream oftherenin gene along with their cognate transcription factors (and specific ligands), co-activators, and co-repressors play a major role in controlling the cell- and tissue-specificity of expression and thetranscriptional responses to physiological cues. We will build upon the progress and major scientificachievements ofthe current budget period to dramatically expand our knowledge on the regulation of reningene expression by: 1) examining the relevance and role of CREB/ATF and HoxDIO transcription factors onthe mechanisms of renin expression in renin expressing cells both in vitro and in vivo; 2) examining cellularand transcriptional mechanisms regulating renin gene by oxidative stress; 3) identifying the function ofconserved non-coding sequences upstream ofthe kidney enhancer using cell lines and recombineeringfollowed by BAC-mediated transgenesis; 4) assessing the novel role of micro RNAs (miRNAs) in theregulation of renin in vitro and in vivo; and 5) examining the importance of brain renin in the regulation ofhydromineral balance and energy metabolism.
Renin is the first and rate limiting step in the production of angiotensin peptides which have pleiotropiceffects on blood pressure, sodium and water homeostasis, sympathetic nervous system and systemicmetabolism. These studies will link transcriptional signals regulating the renin gene with physiologicalendpoints controlling blood pressure and metabolism which may go awry in hypertension.I
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