MicroRNAs as physiological and pathological regulators of cholesterol homeostasis

描述（由申请人提供）：胆固醇的代谢是一种重要的细胞膜成分和代谢途径的前体，在细胞和组织水平上都受到严格调节。胆固醇水平不足或过高会导致病理过程，因此需要对细胞和组织的胆固醇可用性进行复杂的稳态调节。然而，人们对胆固醇流入和流出的复杂过程如何协调调节以维持胆固醇稳态仍然知之甚少。MicroRNAs是一种小的内源性rna，作为生理过程的转录后调节因子而出现。这些短的双链rna在基因组中编码，并结合到mRNA的3‘非翻译区（3’ utr）的互补靶点上，导致翻译抑制和/或mRNA不稳定。值得注意的是，单个miRNA可以有多个靶点，从而提供了一种同时调节参与特定途径或生理过程的基因转录后表达的机制。我们推测microRNAs可能在胆固醇代谢基因通路的表观遗传调控中发挥重要作用。为了深入了解microRNAs在胆固醇代谢中的作用，我们对细胞胆固醇含量调节的microRNAs进行了无偏倚的全基因组筛选。我们确定了靶向调节低密度脂蛋白（LDL）和高密度脂蛋白（HDL）通路成分的mirna。在这项资助中，我们建议确定这些microrna在胆固醇调节的生理和病理过程中的作用。具体来说，我们将使用过表达和拮抗方法：(1)评估这些microrna在调节脂蛋白代谢中的作用，(2)确定它们对动脉粥样硬化进展和消退的影响。这些研究将深入了解microrna对胆固醇稳态转录后调控的作用机制，并评估其作为心血管疾病治疗靶点的潜力。！

DESCRIPTION (provided by applicant): The metabolism of cholesterol, an essential cell membrane component and precursor in metabolic pathways, is tightly regulated at both the cellular and organismal level. Insufficient or excessive cholesterol levels result in pathologic processes, thereby necessitating a complex homeostatic regulation of cholesterol availability to cells and tissues. However, it remains poorly understood how the intricate processes of cholesterol influx and efflux are coordinately regulated to maintain cholesterol homeostasis. MicroRNAs are small endogenous RNAs that have emerged as post- transcriptional regulators of physiological processes. These short, double stranded RNAs are encoded in the genome and bind to complementary target sites in the 3' untranslated regions (3'UTR) of mRNAs, causing translational repression and/or mRNA destabilization. Notably, a single miRNA can have multiple targets, thus providing a mechanism for simultaneously regulating the post-transcriptional expression of genes involved in a specific pathway or physiological process. We hypothesize that microRNAs may play important roles in the epigenetic regulation of cholesterol metabolism gene pathways. To gain insight into role of microRNAs in cholesterol metabolism, we undertook an unbiased genome-wide screen of microRNAs modulated by cellular cholesterol content. We identified miRNAs that target components of the pathways regulating both low density lipoprotein (LDL) and high density lipoprotein (HDL). In this grant, we propose to determine the role of these microRNAs in both the physiological and pathological processes of cholesterol regulation. Specifically we will use overexpression and antagonism approaches to: (1) assess the role of these microRNAs in regulating lipoprotein metabolism, and (2) determine their impact on atherosclerosis progression and regression. These studies will provide insight into the mechanisms by which microRNAs contribute to the post-transcriptional regulation of cholesterol homeostasis, and assess their potential as therapeutic targets in the treatment of cardiovascular disease. ! PUBLIC HEALTH RELEVANCE: Atherosclerotic vascular disease is a major health problem in the US and the western world. This project will advance our understanding of the pathways that regulate LDL and HDL cholesterol metabolism, two independent risk factors for atherosclerosis. These studies may uncover novel therapeutic strategies for the treatment of cardiovascular disease.