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

表观遗传调节因子 Prdm16 控制平滑肌表型调节和动脉粥样硬化风险

• 批准号: 10537602
• 负责人: Brian T. Palmisano
• 金额: $ 7.42万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-19 至 2026-02-18
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537602
• 关键词: Adipose tissue; Affect; Atherosclerosis; Bioinformatics; Blood Vessels; Cause of Death; Cell Lineage; Cell Proliferation; Cell physiology; Cells; Cellular biology; Chromatin; Clinical; Coronary; Coronary Arteriosclerosis; Coronary artery; Data; Development; Disease Resistance; Dyslipidemias; Epigenetic Process; Foundations; Gene Expression; Genes; Genetic; Genetic Translation; Genomics; Glucose; Glycosylated hemoglobin A; Goals; Human; Hypertension; In Vitro; Inflammatory; Informatics; Insulin; Insulin Resistance; Laboratories; Link; Lipids; MADH3 gene; Measures; Metabolic; Metabolic syndrome; Metabolism; Molecular; Molecular Biology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Physicians; Plasma; Play; Proliferating; Regulation; Resolution; Risk; Risk Factors; Role; SKI gene; Scientist; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; Techniques; Technology; Testing; Tissues; Transcriptional Regulation; Vascular Smooth Muscle; Waist-Hip Ratio; Work; XCL1 gene; atherosclerosis risk; career development; causal variant; conditional knockout; disorder risk; epigenetic regulation; fasting glucose; gene discovery; gene network; gene regulatory network; genomic locus; histone methyltransferase; in vivo; inflammatory marker; insight; knock-down; migration; mouse model; novel; novel therapeutics; prevent; response; single cell sequencing; single-cell RNA sequencing; skills; therapy development; trait; transcriptome

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.

项目摘要 冠状动脉疾病（CAD）是世界范围内导致死亡的主要原因，这凸显了迫切需要 此外，肥胖症和 2 型糖尿病的发病率急剧上升。 过去 50 年来，糖尿病 (T2D) 可能会阻碍 CAD 治疗的进展。肥胖会导致胰岛素的产生。 耐药性，通过 T2D 和 T2D 的发展，直接和间接增加了 CAD 的风险 通过代谢综合征的相关异常——血脂异常、高血压、高腰臀 胰岛素抵抗和代谢综合征的治疗方法很少。 尽管还发现了超过 200 个与此相关的基因位点，但它还影响了美国近 30% 的人口。 CAD 和 >320 个与胰岛素抵抗相关代谢特征相关的位点，这些遗传的翻译 由于缺乏对其机制的了解，对基因驱动疗法的深入了解一直停滞不前 该提案旨在确定 CAD 与胰岛素抵抗之间的联系。 基因 PRDM16（PR 结构域包含 16）的连接，该基因与 CAD 和胰岛素相关 PRDM16 与动脉粥样硬化相关的代谢特征相关，已知可通过调节胰岛素抵抗。 然而，PRDM16 在动脉粥样硬化中的作用是调节棕色和米色脂肪组织的功能。 由于 PRDM16 在血管组织和 CAD 中高表达，因此它是 CAD 中一个有前途的致病基因。 平滑肌细胞 (SMC)；与 SMC 功能标记物的高度相关性； CAD基因座；及其与重要的CAD信号通路的相互作用。 PRDM16 通过调节 SMC 的基因网络的表观遗传调控来促进 CAD 风险 申请人的主要发起人 Tom Quertermous 博士拥有促进动脉粥样硬化风险的表型。 开发了 SMC 表型调节的范例，其中 SMC 去分化、增殖和迁移 该范例是使用高分辨率单细胞测序开发的。 利用该平台，该应用程序将通过两个提出的目标来测试他们的假设。 目标1，申请人将确定Prdm16对动脉粥样硬化中血管SMC功能的影响。 2、申请人将使用单细胞确定Prdm16对SMC表型调节的影响 申请人将使用 Prdm16 的新型小鼠模型来测试这些目标。 从 SMC 中删除以及通过在互补体外使用 PRDM16 的分子扰动 拟议的工作将发现 PRDM16 在动脉粥样硬化和动脉粥样硬化中的因果作用。 此外，这项工作将确定 PRDM16 在血管 SMC 生物学中的基本作用。 将 CAD 和胰岛素抵抗联系起来，这将为发现新疗法奠定基础 可治疗 CAD 和胰岛素抵抗。