The goal of Proiect 2 is to examine a novel role of microRNA miR-214 in the development of salt-sensitive hypertension and renal injury. Increased blood pressure salt-sensitivity is a prominent feature in certain populations of hypertensive patients, especially hypertensive African Americans. The molecular mechanism underlying salt-sensitive hypertension and renal injury remains largely unclear. The Dahl salt-sensitive (SS) rat is a widely used animal model of human salt-sensitive forms of hypertension and renal injury. The consomic SS.13[BN] rat and the congenic SS.13[BN26] rat have chromosome 13 (chr 13) or a segment of chr 13 from the Brown Nonway (BN) rat substituted into the SS genome. These rat strains exhibit significantly attenuated saltinduced hypertension and renal injury, and have been highly valuable for studying the disease phenotypes in the SS rat. MicroRNAs are endogenous, regulatory RNAs. Numerous recent studies have demonstrated that microRNAs represent one of the most important mechanisms for the regulation of gene expression and play crucial roles in a wide range of physiological processes and diseases including cardiovascular and renal functions. However, it remains largely unknown if or how microRNAs contribute to the regulation of arterial blood pressure or related tissue injury. We have found that microRNA miR-214, which is located in the SS.13[BN26] congenic region, was up-regulated in the kidneys of the SS rat compared to SS.13[BN26] and SS.13[BN26] rats. Several lines of exciting preliminary evidence suggest that miR-214 might play a significant and novel role in salt-sensitive hypertension and renal injury both in SS rats and in patients. We hypothesize that miR-214 contributes to the development of salt-sensitive hypertension and renal injury. We propose to test the hypothesis in four specific aims.
Aim 1 will examine the functional contribution of miR-214 to salt-sensitive hypertension and renal injury in the SS rat.
Aim 2 will investigate possible downstream mechanisms mediating the effect of miR-214.
Aim 3 will examine upstream trans and cis regulatory mechanisms underiying the up-regulation of miR-214 in the SS rat.
Aim 4 will complete a pilot study of the clinical relevance of miR-214 in human salt-sensitive hypertension and renal injury. Project 2 will use several state-of-the-art approaches and techniques to examine the innovative concept that non-protein-coding genes may play important roles in hypertension and related tissue injury. Project 2 will unitilize data from Project 1, feed new data into the network construction in Project 1, share technological advances in proteomics and promoter analysis with Project 3, and contribute to the overall goal of the PPG, which is achieving a significantly deeper understanding of the molecular pathophysiology of hypertension, renal injury, and angiogenesis. Project 2 will benefit greatly from genomic, genetic, proteomic, computational and animal research technological advances provided in Cores B and C.
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