The Epigenetic Regulator Prdm16 Controls Smooth Muscle Phenotypic Modulation and Atherosclerosis Risk

项目摘要 冠状动脉疾病(CAD)是世界范围内主要的死亡原因，突出了对 除了目前可用的治疗方法之外，还有其他治疗方法。此外，肥胖症和II型的急剧上升 糖尿病(T2D)威胁着过去50年来冠心病治疗的进展。肥胖导致胰岛素 耐药性，这直接和间接地增加了CAD的风险，通过T2D和 通过代谢综合征的相关异常--血脂异常、高血压、高腰臀 比率，和高血糖。几乎没有治疗胰岛素抵抗和代谢综合征的方法。 尽管影响了美国近30%的地区。此外，尽管发现了与&gt；200个遗传位点相关的 与胰岛素抵抗相关的代谢性状相关的CAD和&gt；320基因座的翻译 由于缺乏对机制的理解，对基因驱动疗法的洞察一直停滞不前。 冠心病与胰岛素抵抗的关系。这项建议旨在确定 与冠心病和胰岛素相关的基因PRDM16(PR结构域包含16)的连接 抵抗力相关的代谢性状，对动脉粥样硬化。已知PRDM16通过以下途径调节胰岛素抵抗 棕色和米色脂肪组织功能的调节。然而，PRDM16在动脉粥样硬化中的作用是 未知。PRDM16在血管组织和血管组织中的高表达是一个很有前途的冠心病病因基因 平滑肌细胞(SMC)；它与SMC功能标志物高度相关；它与其他已知的 以及它与重要的CAD信号通路的相互作用。申请者的中心假设是 PRDM16通过对调节SMC的基因网络的表观遗传调节而增加冠心病风险 表型可增加动脉粥样硬化的风险。申请者的主要赞助人汤姆·奎特莫斯博士 发展了一种SMC表型调节的范例，SMC通过该范例去分化、增殖和迁移 对致动脉粥样硬化刺激的反应。这一范例是使用高分辨率单细胞测序开发的 技术。利用这一平台，该应用程序将通过两个提出的目标来测试他们的假设。在……里面 目的1、研究Prdm16在动脉粥样硬化中对血管SMC功能的影响。在AIM 2、申请人将确定Prdm16对使用单细胞的SMC表型调制的影响 测序技术。申请者将使用一种新的鼠标模型来测试这些目标，Prdm16是 从SMC中删除以及利用PRDM16在体外互补中的分子扰动 接近了。这项拟议的工作将发现PRDM16在动脉粥样硬化中的因果作用以及 PRDM16在血管SMC生物学中的基础作用。此外，这项工作还将确定一条新的途径 将CAD和胰岛素抵抗联系起来，这将为发现新的疗法奠定基础 可以同时治疗冠心病和胰岛素抵抗。

PROJECT ABSTRACT Coronary artery disease (CAD) is the worldwide leading cause of death, highlighting a critical need for additional therapies beyond what is currently available. Furthermore, the dramatic rise in obesity and type 2 diabetes (T2D) threatens to derail progress in treatment of CAD over the last 50 years. Obesity causes insulin resistance, which increases the risk of CAD both directly and indirectly, through the development of T2D and through the associated abnormalities of the metabolic syndrome – dyslipidemia, hypertension, high waist-hip ratio, and elevated glucose. There are few treatments available for insulin resistance and metabolic syndrome despite affecting nearly 30% of the US. Additionally, despite discovery of >200 genetic loci associated with CAD and >320 loci associated with insulin resistance related metabolic traits, the translation of these genetic insights into genetically driven therapies has been stagnated by the lack of understanding of the mechanistic connection between of CAD and insulin resistance. This proposal aims to determine the mechanistic connection of the gene PRDM16 (PR domain containing 16), which is associated with both CAD and insulin resistance related metabolic traits, to atherosclerosis. PRDM16 is known to regulate insulin resistance through regulation of brown and beige adipose tissue function. However, the role of PRDM16 in atherosclerosis is unknown. PRDM16 is a promising causal gene in CAD due to its high expression in vascular tissues and smooth muscle cells (SMCs); its high correlation with markers of SMC function; its interaction with other known CAD loci; and its interaction with important CAD signaling pathways. The applicant’s central hypothesis is that PRDM16 promotes CAD risk through epigenetic regulation of gene networks that modulate SMC phenotype to promote atherosclerosis risk. The applicant’s primary sponsor, Dr. Tom Quertermous, has developed a paradigm of SMC phenotypic modulation whereby SMCs de-differentiate, proliferate and migrate in response to atherogenic stimuli. This paradigm was developed using high resolution single cell sequencing technologies. Leveraging this platform, the application will test their hypothesis through two proposed aims. In Aim 1, the applicant will determine the impact of Prdm16 on vascular SMC function in atherosclerosis. In Aim 2, the applicant will determine the impact of Prdm16 on SMC phenotypic modulation using single cell sequencing technologies. The applicant will test these aims using a novel mouse model whereby Prdm16 is deleted from SMCs as well as by using molecular perturbations of PRDM16 in complementary in-vitro approaches. The proposed work will discover the causal role of PRDM16 in atherosclerosis and the fundamental role of PRDM16 in vascular SMC biology. Additionally, this work will identify a novel pathway connecting both CAD and insulin resistance, which will lay the foundation for discovery of novel therapies that may treat both CAD and insulin resistance.