Endothelial Cell Health Across the Spectrum of Cardiometabolic Disease

整个心血管代谢疾病范围内的内皮细胞健康

• 批准号: 10681949
• 负责人: Naomi Miriam Hamburg
• 金额: $ 75.29万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-12 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681949
• 关键词: Acceleration; Adult; Age Distribution; Aging; Atherosclerosis; Automobile Driving; Basic Science; Bioinformatics; Biological; Biology; Biopsy; Blood Vessels; Body mass index; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Cell Line; Clinical; Communities; Complement; Data; Development; Diabetes Mellitus; Disease; Drug Modulation; Dwarfism; Endoplasmic Reticulum; Endothelial Cells; Endothelium; Event; Framingham Heart Study; Functional disorder; Future; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genetic Transcription; Genomic approach; Glucose; Health; Heart Diseases; Human; Immunofluorescence Immunologic; Individual; Insulin Resistance; Life; Link; Longitudinal cohort study; Measures; Metabolic; Metabolism; Mitochondria; Molecular; Nested Case-Control Study; Nitric Oxide; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated cardiovascular disease; Organelles; Participant; Pathway Analysis; Pathway interactions; Pattern; Phenotype; Population Sciences; Prevalence; Preventive; Procedures; Public Health; RNA analysis; Research; Research Personnel; Resources; Risk; Risk Factors; Sampling; Sex Distribution; Signal Transduction; Stress; Therapeutic; Transcript; Vascular Diseases; Vascular Endothelium; Venous; Work; cardiometabolic risk; cardiometabolism; cardioprotection; cardiovascular disorder risk; cardiovascular health; cardiovascular risk factor; case control; clinical development; clinical phenotype; cohort; differential expression; endoplasmic reticulum stress; endothelial dysfunction; experience; experimental study; fitness; genomic biomarker; innovation; insight; metabolomics; middle age; minimally invasive; mitochondrial dysfunction; multidisciplinary; multiple omics; novel; novel strategies; patient oriented research; premature; programs; prospective; public health relevance; trait; transcriptome sequencing; transcriptomics; vascular injury

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.

项目总结/摘要 包括肥胖和2型糖尿病在内的心脏代谢危险因素的患病率不断上升 （T2 DM）提出了一个关键的心血管挑战。患有心脏代谢疾病的个体 心血管疾病（CVD）风险，包括加速血管老化和过早动脉粥样硬化 疾病重要的是，内皮功能的改变早于临床CVD的发展， 血管内皮是心脏保护的重要潜在靶点。实验研究和我们先前的 工作链接改变代谢细胞器的压力，包括线粒体功能障碍和ER压力。在这 因此，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CVD。我们将利用计划中的心脏病研究的独特资源， 检查周期，以从2000个个体中前瞻性地收集新鲜的人内皮细胞（EC）。在目标1中， 我们将研究2型糖尿病和心脏代谢特征与EC表型的关系，包括细胞器 压力和一氧化氮信号在巢式病例对照样本的450人。在目标2中，我们将测量 在900名参与者中使用RNA测序的EC基因表达水平，以识别和优先考虑EC 与EC健康表型、心脏代谢性状和全身代谢相关的转录程序。这 该提案利用了一个独特的、经验丰富的多学科调查人员团队，他们在以下方面具有专门知识： 肥胖相关心血管疾病，内皮生物学，人口科学，转化患者导向 研究、多组学和生物信息学。这项拟议中的工作将使过去定义内皮细胞的努力相形见绌。 并将联合收割机结合大规模进行的EC新的深度表型分析， 基于社区的队列，现有严格的心血管健康指标，包括代谢产物谱 和基因组标记。这些研究有可能为驱动机制提供重要见解 内皮功能障碍和开发一个前所未有的资源，将有利于血管生物学研究。