RNA-binding proteins in atherosclerosis

项目总结/摘要 胆固醇稳态的紊乱是心血管疾病和相关疾病的主要原因。 合并症。这项提案的目的是确定RNA结合蛋白在胆固醇中的作用， 代谢和动脉粥样硬化。RNA结合蛋白和非编码RNA之间的相互作用可能会影响 转录输出在特定的遗传邮政编码，无论是本地或跨多个染色体。 为了加强这一前提，我们的初步研究表明，转录辅激活因子和RNA结合 蛋白Raly与非编码RNA LeXis相互作用，调节胆固醇生物合成的表达， 基因.利用这一新的见解，我们的目标是调查的贡献RALY甾醇代谢。 在目的1中，我们定义了Raly在胆固醇代谢中的生理作用和对动脉粥样硬化的贡献 发展我们将通过研究具有组织特异性Raly缺失的小鼠或 用获得或丧失功能的腺病毒载体转导。在目标2中，我们将通过以下方式研究机制： RALY影响基因表达。利用无偏的全基因组方法将绘制潜在的Raly 结合位点，其对染色质结构的影响，并破译其合作和等级关系 与转录调节剂。这些研究有望揭示机制的基本见解 控制代谢调节，同时探索治疗干预的新机会。

PROJECT SUMMARY/ABSTRACT Perturbations in cholesterol homeostasis are major contributors to cardiovascular disease and associated comorbidities. The objective of this proposal is to define the role of RNA-binding proteins in cholesterol metabolism and atherosclerosis. Interactions between RNA-binding proteins and non-coding RNAs may affect transcriptional outputs at specific genetic zip codes, either locally or across multiple chromosomes. Reinforcing this premise, our preliminary studies suggest that the transcriptional coactivator and RNA-binding protein Raly interacts with the noncoding RNA LeXis to modulate the expression of cholesterol biosynthetic genes. Capitalizing on this novel insight, we aim to investigate the contributions of RALY in sterol metabolism. In Aim 1, we define the physiologic role of Raly in cholesterol metabolism and contributions to atherosclerosis development. We will test out hypotheses by studying mice with tissue specific deletion of Raly or mice transduced with gain- or loss-of-function adenoviral vectors. In Aim 2, we will investigate the mechanisms by which RALY influences gene expression. Utilizing unbiased genome wide approaches will map potential Raly binding sites, its influence on chromatin architecture and decipher its cooperative and hierarchical relationship with transcriptional modulators. These studies are expected to shed fundamental insight into mechanisms controlling metabolic regulation while exploring novel opportunities for therapeutic intervention.