DIET AND GENOTYPE IN PRIMATE ATHEROSCLEROSIS

灵长类动脉粥样硬化的饮食和基因型

• 批准号: 7957880
• 负责人: JOHN L VANDEBERG
• 金额: $ 99.77万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-06 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957880
• 关键词: Adipose tissue; Animal Model; Arterial Fatty Streak; Atherosclerosis; Biopsy; Blood Vessels; Cell physiology; Cells; Characteristics; Cholesterol; Chronic; Clinical; Computer Retrieval of Information on Scientific Projects Database; Diet; Dietary Component; Dietary Factors; Dietary Fats; Disease; Dyslipidemias; Endothelial Cells; Experimental Genetics; Fatty acid glycerol esters; Functional disorder; Funding; Gene Expression Profiling; Genes; Genetic; Genome; Genomics; Genotype; Goals; Grant; Human; Hypertension; In Vitro; Individual; Institution; Lead; Lipoproteins; Lymphocyte; Measures; Modeling; Molecular Profiling; Obesity; Papio; Peripheral; Phenotype; Phylogenetic Analysis; Physiological; Predisposition; Primates; QTL Genes; Quantitative Trait Loci; Research; Research Personnel; Research Project Grants; Resources; Risk; Risk Factors; Services; Signal Transduction; Source; Stem cells; United States National Institutes of Health; Variant; data management; design; femoral artery; follow-up; genome wide association study; oxidative damage; positional cloning; programs; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This research program uses the pedigreed baboon model to investigate the interactions of diet and genotype to determine variation in phenotypes related to macrovascular endothelial cell (EC) function, lipoproteins, oxidative damage, adiposity, and other risk factors for atherosclerosis. The overall goal of this program is to identify genes that contribute to variation in these phenotypes, and to define genotype ¿ diet interactions that influence them. To achieve this goal, we will continue genome-wide scans to localize relevant genes, follow up previously detected linkage signals in order to identify the quantitative trait loci (QTLs) that are responsible for the signals, and determine the effects of a chronic high cholesterol, high fat (HCHF) dietary challenge on the expression of atherosclerotic risk factors and vascular function. Project 1 will isolate and culture ECs from biopsied femoral arteries of pedigreed baboons. These cells will be subjected to in vitro pro-atherogenic challenges. We will assess the genetics of response to these challenges by quantifying EC dysfunction markers measured before and after the cells are challenged. Project 1 also will assess the genetic control of the number of circulating endothelial progenitor cells (CEPCs); and the relationships between EC functional characteristics, number and differentiation capacity of CEPCs, and extent of atherosclerotic lesions after the HCHF challenge. Project 2 will identify and compare networks of genes underlying variation in clinical risk factors and transcriptional profiles in peripheral lymphocytes and ECs from baboons on basal diet with those following the chronic dietary challenge. Project 3 will focus on identifying genes for QTLs influencing phenotypes related to dyslipidemia, oxidative damage and hypertension using chromosomal region specific gene expression profiling, positional cloning, statistical genomic analysis and whole genome expression profiling. Project 4 will detect and localize genes that influence adiposity and adipokine expression, and will evaluate the effects of the HCHF challenge on adipose tissue and muscle and their relationships to risk of atherosclerosis. The research projects are supported by four core units that provide phenotyping, data management and computing, veterinary services, and administrative services. The physiological similarity and the close phylogenetic relationship between baboons and humans make the baboon well suited as an animal model for atherosclerosis. The use of baboons enables controlled genetic and experimental manipulations designed to detect genetic effects and interactions that may be difficult or impossible to identify in humans. In addition, the mechanisms of action of these genes and their interactions with dietary components can be established experimentally. This research will lead to a better understanding of the genes that control susceptibility to atherosclerosis and how they interact with dietary factors to determine individual susceptibility to this disease.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 中心，不一定是研究者的机构。 该研究项目使用纯种狒狒模型来研究饮食和基因型的相互作用，以确定与大血管内皮细胞（EC）功能、脂蛋白、氧化损伤、肥胖和其他动脉粥样硬化危险因素相关的表型变异。计划的目的是识别导致这些表型变异的基因，并定义基因型 ¿为了实现这一目标，我们将继续进行全基因组扫描以定位相关基因，跟踪先前检测到的连锁信号，以确定影响它们的数量性状基因座（QTL）。 项目 1 将从纯种狒狒的股动脉活检中分离和培养这些细胞。将受到体外 我们将通过量化细胞受到攻击之前和之后测量的 EC 功能障碍标记物来评估对这些挑战的反应的遗传学；项目 1 还将评估循环内皮祖细胞 (CEPC) 数量的遗传控制； HCHF 挑战后 EC 功能特征、CEPC 的数量和分化能力以及动脉粥样硬化病变程度之间的关系将识别和比较临床危险因素和转录谱变化背后的基因网络。项目 3 将重点利用染色体区域特异性基因表达谱、位置克隆、统计基因组来鉴定影响血脂异常、氧化损伤和高血压相关表型的 QTL 基因。项目 4 将检测和定位影响肥胖和脂肪因子表达的基因，并评估 HCHF 挑战的影响。这些研究项目由提供表型分析、数据管理和计算、兽医服务和行政服务的四个核心单位支持。 狒狒与人类之间的生理相似性和密切的系统发育关系使狒狒非常适合作为动脉粥样硬化的动物模型。狒狒的使用可以进行受控的遗传和实验操作，旨在检测在人类中很难或不可能识别的遗传效应和相互作用。此外，这些基因的作用机制及其与饮食成分的相互作用可以通过实验建立，这项研究将有助于更好地了解控制动脉粥样硬化易感性的基因及其相互作用。结合饮食因素来确定个体对这种疾病的易感性。