Epoxyeicosatrienoic acids, diabetes, and cardiovascular disease

环氧二十碳三烯酸、糖尿病和心血管疾病

基本信息

批准号：
9195147
负责人：
Rozenn Lemaitre
金额：
$ 70.28万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-15 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9195147
关键词：
Acids American Indians Anabolism Animal Model Apoptosis Arachidonic Acids Atherosclerosis Brain CYP2J2 gene Calcium Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cardiovascular system Clinical Communities Coronary heart disease Coupling Cytochrome P450 Data Development Diabetes Mellitus Disease Down-Regulation Elderly Enzymes Epidemic Epoxide hydrolase Exposure to Family Study Fasting Functional disorder Future Genetic Polymorphism Genetic Transcription Glucose Glycosylated hemoglobin A Heart Heart failure Human In Vitro Insulin Insulin Resistance Ischemic Stroke Islet Cell Isomerism Link Lipids Mass Spectrum Analysis Measures Mediating Metabolic Metabolic Marker Metabolic stress Metabolism Methodology Modeling Morbidity - disease rate Muscle Cells Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress PPAR gamma Pancreas Participant Pathway interactions Patients Plasma Population Study Prevention Prospective Studies Public Health Reactive Oxygen Species Regulation Risk Risk Factors Role Sampling Serum Stimulus Stroke Structure of beta Cell of islet System Testing Time Tribes Vascular Endothelium Ventricular base cardiovascular health cardiovascular risk factor cohort diabetes risk diabetic diabetic patient early onset experimental study fasting glucose fighting follow-up genetic association glucose tolerance high risk high risk population improved in vivo innovation insight insulin secretion mortality novel overexpression population based prevent prospective public health relevance response transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Type 2 diabetes has reached epidemic proportions world-wide and carries a high burden of cardiovascular morbidity and mortality. This application seeks to identify novel modifiable factors, namely plasma epoxyeicosatrienoic acid (EET) species, associated with risks of incident diabetes and diabetes-associated incident cardiovascular disease. In addition, we will study the influence of serum from diabetic patients on EET metabolism and regulation in human cardio-myocytes. EETs are arachidonic acid derivatives with important functions in vascular endothelium, pancreas, heart and brain. In animal models of diabetes or insulin resistance, increased EET levels from overexpression of CYP2J2 or inhibition of soluble epoxide hydrolase, reduce glucose and insulin levels, improve glucose tolerance, improve insulin secretion and reduce islet cell apoptosis, suggesting a potentially important role in the pathophysiology of diabetes. In addition, manipulation of EET levels in animal models has linked these metabolites to the development of atherosclerosis, heart failure, myocardial ischemia and reperfusion, stroke and cardiomyopathy. These findings together with evidence from genetic association studies in humans led us to hypothesize that plasma EETs are associated with lower risks of incident diabetes and diabetes-related cardiovascular disease. We will investigate these hypotheses in two prospective studies, the Strong Heart Family Study, a community-based, prospective study of risk factors for cardiovascular disease among American Indians from 13 different tribes, and the Cardiovascular Health Study, a prospective study of risk factors for cardiovascular disease among older adults. Using state-of-the-art methodology, we will measure 4 EET species in plasma from existing samples from 4000 total study participants, and combine these new data with existing information on risk factors and follow-up data to examine the following specific aims: (Aim 1) To prospectively examine the associations of EETs with incident diabetes (Aim 1a), changes in fasting glucose, fasting insulin, HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) and hemoglobin A1C among participants without diabetes (Aim1b), and with incident cardiovascular disease (including myocardial infarction, ischemic stroke, and heart failure) among participants with diabetes (Aim 1c). In Aim 2, we will use an in vitro system to investigate whether CYP2J2 down regulation, resulting in lower EETs, contributes to human cardio-myocyte metabolic stress during type 2 diabetes, and we will identify CYP2J2- regulated pathways mediating the response to diabetes. Collectively, these complementary aims will determine the associations between EETs and risks of incident diabetes and diabetes-associated CVD, while also identifying mechanisms through which diabetes perturbs EET pathways and promotes cardio-myocyte dysfunction. By linking clinically meaningful endpoints with mechanistic insights, this project creates a roadmap for innovative approaches to prevent and treat diabetes and its complications.

描述（由申请人提供）：2型糖尿病已在全球范围内达到流行比例，并承担着高负重的心脏疾病和死亡率。 - 与糖尿病的动物，胰腺，心脏和大脑中重要功能的人类心脏损伤中相关的心血管疾病。葡萄糖和胰岛素水平，改善葡萄糖耐受并减少液压性，在糖尿病的病理生理学中可能起作用，在动物模型中操纵EET水平已将代谢物与动脉粥样硬化，心脏衰竭，心脏失败，心肌性局部缺血和心脏病联系在一起。这些发现从人类的遗传研究中的迫切性使我们假设与糖尿病相关的心血管疾病风险较低有关的血浆EET与两种前瞻性研究中的假设相关。来自13个不同部落的印第安人和心血管健康研究，这是使用最先进的成年人的心血管脱离的危险因素。，并将这些NEWTA与现有的风险因素和后续数据相结合以检查以下特定目的：（目标1以前瞻性地检查EET与入射糖尿病的关联（AIM 1A），禁食葡萄糖的变化，禁食胰岛素，HOMA-- IR（胰岛素抵抗的稳态模型评估）和糖尿病参与者中的血红蛋白A1C（AIM1B）H入射心血管疾病，我们将使用体外系统进行研究，从而导致较低的EET 2型糖尿病期间的压力，我们将确定与CYP2J2型的途径共同介导对糖尿病的反应，TESE互补的目标将确定与糖尿病相关的事件的关联和风险，同时还确定了肌细胞心肌细胞和心形的肌细胞cardio-Myocytes l Endocys l Enspoints l Endointes l endoctess l endocyss l endointss l endointss l endoctss l endointss。机械洞察力，该项目为预防和治疗糖尿病及其复杂性的创新方法创建了路线图。