microRNA-mRNA Interaction Networks in Arterioles in Type 2 Diabetes
The goal of the proposed project is to identify alternations in the microRNA-target gene network that may contribute to the development of microvascular endothelial dysfunction in type 2 diabetes mellitus (T2DM) in human. The microvascular complications of T2DM are leading causes of renal failure, physical disability and amputations, and blindness in the United States. Endothelial dysfunction is an early event in the development of microvascular complications and can predict future adverse vascular events. The lack of a detailed understanding of the genomic and molecular mechanism underlying endothelial dysfunction is a key knowledge gap limiting our understanding of how to mitigate the microvascular complications of T2DM. MicroRNAs are endogenous, regulatory RNAs that primarily reduce protein expression by binding to the 3’-untranslated region (UTR) of target mRNAs. Numerous recent studies have demonstrated that microRNAs play crucial roles in a wide range of physiological processes and diseases including the development of diabetes and diabetic complications in animal models. However, it remains largely unknown if or how microRNAs contribute to the development of microvascular complications of diabetes in humans. We hypothesize that the microRNA-target gene interaction network is altered in endothelial cells in small resistance vessels in patients with T2DM, which contribute to the development of endothelial dysfunction and microvascular complications in these patients. The proposed pilot project represents the first step in testing the hypothesis. Specifically, we will use next-generation sequencing to obtain mRNA and microRNA abundance profiles in endothelial cells in small resistance vessels from T2DM patients and control subjects (Aim 1) and construct microRNA-mRNA interaction networks using Bayesian graphical modeling (Aim 2).

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