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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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（T2DM）带来了严峻的心血管挑战。患有心脏代谢疾病的人具有更大的心血管疾病（CVD）的风险，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心血管疾病的发展，使得血管内皮是心脏保护的重要潜在靶点。实验研究和我们之前的研究研究人员将代谢改变与细胞器应激（包括线粒体功能障碍和内质网应激）联系起来。在这个建议，我们假设心脏代谢特征引起的细胞器应激会导致血管功能障碍并促进CVD。我们将利用计划中的弗雷明汉心脏研究第四期的独特资源检查周期前瞻性地从 2000 名个体中收集新鲜的人内皮细胞 (EC)。在目标 1 中，我们将研究 T2DM 和心脏代谢特征与 EC 表型（包括细胞器）的关联 450 人的嵌套病例对照样本中的压力和一氧化氮信号。在目标 2 中，我们将测量使用 RNA 测序对 900 名参与者进行 EC 基因表达水平识别和优先排序与 EC 健康表型、心脏代谢特征和全身代谢相关的转录程序。这提案利用了一个独特且经验丰富的多学科研究团队，他们具有以下方面的专业知识：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。拟议的工作将使过去定义内皮细胞的努力相形见绌。跨疾病状态的健康状况，并将结合大规模进行的 EC 的新深度表型分析基于社区的队列，具有现有严格的心血管健康指标，包括代谢特征和基因组标记。这些研究有可能为驱动机制提供重要见解内皮功能障碍并开发一种前所未有的资源，将有利于血管生物学研究。