Endothelial Cell Health Across the Spectrum of Cardiometabolic Disease

项目摘要/摘要 肥胖和2型糖尿病等心脏代谢危险因素的患病率不断上升 (T2 DM)是一个严重的心血管挑战。患有心脏代谢性疾病的人 心血管疾病(CVD)的风险，包括血管加速老化和过早的动脉粥样硬化 疾病。重要的是，内皮功能的改变早于临床心血管疾病的发展，使 血管内皮细胞是心脏保护的重要潜在靶点。实验研究和我们之前的 工作将代谢改变与细胞器应激有关，包括线粒体功能障碍和内质网应激。在这 建议，我们假设由心脏代谢特征引起的细胞器应激导致血管功能障碍。 并促进心血管疾病。我们将利用计划中的第四项弗雷明翰心脏研究的独特资源 检查周期预期从2000人中收集新鲜的人内皮细胞(EC)。在目标1中， 我们将研究T2 DM和心脏代谢特征与包括细胞器在内的EC表型的关系 450人嵌套病例对照样本中应激和一氧化氮信号转导。在目标2中，我们将测量 应用RNA测序技术对900名受试者的EC基因表达水平进行鉴定和优先排序 与EC健康表型、心脏代谢特征和系统代谢相关的转录程序。这 Proposal利用了一支独特的、经验丰富的多学科调查团队，他们具有以下专业知识 肥胖相关心血管疾病，血管内皮细胞生物学，人口科学，以患者为导向 研究、多组学和生物信息学。这项拟议的工作将使过去定义内皮细胞的努力相形见绌 跨疾病州的健康，并将结合新的深入的EC表型，在 以社区为基础的队列，现有严格的心血管健康衡量标准，包括代谢物图谱 和基因组标记。这些研究有可能为驱动机制提供重要的见解 并开发一种前所未有的资源，这将有助于血管生物学研究。

Project Summary/Abstract The escalating prevalence of cardiometabolic risk factors including obesity and type 2 diabetes mellitus (T2DM) presents a critical cardiovascular challenge. Individuals with cardiometabolic disease harbor greater risk of cardiovascular disease (CVD) including accelerated vascular aging and premature atherosclerotic disease. Importantly, alterations in endothelial function predate the development of clinical CVD, making the vascular endothelium an important potential target for cardioprotection. Experimental studies and our prior work link altered metabolism to organelle stress including mitochondrial dysfunction and ER stress. In this proposal, we hypothesize that organelle stress induced by cardiometabolic traits drives vascular dysfunction and promotes CVD. We will leverage the unique resources of the planned Framingham Heart Study fourth examination cycle to prospectively collect fresh human endothelial cells (EC) from 2000 individuals. In Aim 1, we will investigate the association of T2DM and cardiometabolic traits with EC phenotype including organelle stress and nitric oxide signaling in a nested case-control sample of 450 individuals. In Aim 2, we will measure EC gene expression levels using RNA sequencing in 900 participants to identify and prioritize EC transcriptional programs linked to EC health phenotypes, cardiometabolic traits, and systemic metabolism. This proposal leverages a unique and highly experienced multidisciplinary team of investigators with expertise in obesity-related cardiovascular disease, endothelial biology, population science, translational patient-oriented research, multi-omics and bioinformatics. The proposed work will dwarf past efforts at defining endothelial health across disease states and will combine new deep phenotyping of EC conducted at scale in a community-based cohort with existing rigorous measures of cardiovascular health including metabolite profiles and genomic markers. These studies have the potential to provide important insights into mechanisms driving endothelial dysfunction and develop an unprecedented resource that will benefit vascular biology research.