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Genetic connections between type 2 diabetes and atherosclerosis

2 型糖尿病与动脉粥样硬化之间的遗传联系

基本信息

批准号：
10319991
负责人：
WEIBIN SHI
金额：
$ 39.89万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-10 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319991
关键词：
Adipose tissue Affect Apolipoprotein E Arterial Fatty Streak Atherosclerosis Attention Blood Glucose Blood Vessels Candidate Disease Gene Cardiovascular system Cessation of life Cholesterol Complex Complications of Diabetes Mellitus Confidence Intervals Congenic Strain Consumption Coronary heart disease Country Development Diabetes Mellitus Disease Environmental Risk Factor Event Exposure to Flow Cytometry Gene Expression Profiling Genes Genetic Genetic Heterogeneity Genetically Engineered Mouse Glucose Glucose Intolerance Growth High Fat Diet Human Human Genome Inbred BALB C Mice Inbred Strain Individual Infiltration Inflammation Inflammatory LDL Cholesterol Lipoproteins Lipids Liver Metabolic Diseases Modeling Mus Myocardial Infarction Names Non-Insulin-Dependent Diabetes Mellitus Pathogenicity Pathway interactions Peripheral arterial disease Persons Phase Phenotype Plasma Population Predisposition Prevention Process Quantitative Trait Loci Research Resistance Risk Role Skeletal Muscle Stroke Testing Tissues Triglycerides Type 2 diabetic United States Work bioinformatics tool causal variant congenic diabetic diabetic patient fasting glucose genetic analysis genetic linkage analysis genetic variant genome wide association study genomic tools glucose metabolism glucose tolerance impaired glucose tolerance interest islet low density lipoprotein triglyceride macrophage mortality mouse model non-diabetic novel strategies prevent recruit resistant strain tool trait western diet

项目摘要

Abstract Diabetic patients have 2~4-fold increased risk of developing atherosclerotic vascular disease and its complications compared to non-diabetic individuals, and individuals with atherosclerosis frequently have type 2 diabetes mellitus (T2DM). Although genetic factors have been well documented as a major determinant of cardiovascular events in type 2 diabetic patients, identification of causal variants has been confounded by both environmental and genetic heterogeneity. We have observed that Apoe-/- mice, a commonly used model for atherosclerosis research, develop T2DM on certain genetic backgrounds after prolonged exposure to a Western diet but become resistant after being transferred on certain other backgrounds. The Apoe-/- strains that are resistant to atherosclerosis have significantly lower non-fasting glucose levels and display greater glucose tolerance than those that are susceptible to atherosclerosis. In an intercross derived from C57BL/6 (B6) and BALB/c (BALB) Apoe-/- mice, we identified a significant QTL for atherosclerosis, named Ath42, which coincides precisely with Bglu13, a major QTL for blood glucose. A congenic strain with a BALB donor segment harboring Bglu13 and Ath42 in the B6-Apoe-/- background showed significant reductions in atherosclerotic lesion size and plasma glucose level. Thus, the hypothesis to be tested is that accelerated atherosclerosis in diabetes is due, in part, to genetic variants that influence both disorders. To test this hypothesis, specific aim 1 will dissect the congenic region harboring Bglu13 and Ath42 through fine mapping to determine whether atherosclerosis and blood glucose are controlled by the same or different causal gene(s). Postprandial glucose levels, rather than fasting glucose, are related to incident myocardial infarction in type 2 diabetic patients. Elevated postprandial glucose levels are frequently accompanied by elevated postprandial levels of LDL cholesterol and triglyceride, which accelerate atherosclerosis. In aim 2, we will characterize a segregating F2 population from phenotypically divergent Apoe-/- strains to partition individual contribution of postprandial glucose versus postprandial lipids to atherosclerotic lesion sizes and identify genetic factors that connect them. Elevated postprandial glucose levels are also accompanied by elevated postprandial inflammation. We have observed significant macrophage infiltration in the islets of Apoe-/- mice fed a Western diet. In aim 3, we will use the F2 population to identify genetic factors affecting macrophage infiltration into the islets as well as postprandial inflammation. The proposed research will lead to identification of genetic factors that connect two important diseases and reveal new targets for prevention and treatment of cardiovascular complications in diabetic patients.

摘要糖尿病患者发生动脉粥样硬化性血管疾病的风险增加2~4倍，与非糖尿病个体和动脉粥样硬化个体相比，患有2型糖尿病（T2 DM）。虽然遗传因素已被充分证明是一个主要的 2型糖尿病患者心血管事件的决定因素，确定因果变异，受到环境和遗传异质性的混淆。我们观察到Apoe-/- 小鼠是动脉粥样硬化研究中常用的模型，背景后，长期暴露于西方饮食，但成为耐后，被转移在其他背景下。抗动脉粥样硬化的ApoE-/-菌株具有显著的较低的非空腹血糖水平，并显示出比那些易受影响的人更大的葡萄糖耐量动脉粥样硬化在C57 BL/6（B6）和BALB/c（BALB）Apoe-/-小鼠的杂交中，我们确定了一个动脉粥样硬化的重要QTL，命名为Ath 42，它与Bglu 13，血糖的主要QTL。具有携带Bglu 13的BALB供体片段的同源株，在B6-Apoe-/-背景中的Ath 42显示动脉粥样硬化病变大小显著减小，血糖水平因此，有待检验的假设是，糖尿病患者动脉粥样硬化加速部分原因是影响这两种疾病的遗传变异。为了验证这一假设，具体目标1 将通过精细作图来解剖Bglu 13和Ath 42的同源区域，以确定是否动脉粥样硬化和血糖由相同或不同的致病基因控制。餐后血糖水平而非空腹血糖与2型糖尿病患者心肌梗死相关患者餐后血糖水平升高通常伴有餐后血糖水平升高。低密度脂蛋白胆固醇和甘油三酯水平，加速动脉粥样硬化。在目标2中，我们表征从表型不同的Apoe-/-菌株中分离的F2群体以进行分区餐后血糖与餐后血脂对动脉粥样硬化病变大小的个体影响并找出与之相关的遗传因素。餐后血糖水平升高也是伴有餐后炎症升高。我们观察到巨噬细胞在喂食西方饮食的Apoe-/-小鼠的胰岛中的浸润。在目标3中，我们将使用F2群体来确定影响巨噬细胞浸润到胰岛以及餐后炎症这项拟议中的研究将导致识别连接两个基因的遗传因素。重要疾病，并揭示预防和治疗心血管并发症的新靶点在糖尿病患者中。