Kruppel-like factor 11 (KLF11) and atherosclerosis

Kruppel 样因子 11 (KLF11) 和动脉粥样硬化

• 批准号: 9924279
• 负责人: Jifeng Zhang
• 金额: $ 45.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924279
• 关键词: Accounting; Address; Adult; American; Anti-Inflammatory Agents; Antiinflammatory Effect; Antioxidants; Aorta; Arterial Fatty Streak; Atherosclerosis; Attenuated; Biology; Blood Vessels; Breeding; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion Molecules; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Cholesterol; Clinical; Combination Medication; Development; Diabetes Mellitus; Diabetic Angiopathies; Diet; Down-Regulation; Endothelial Cells; Endothelium; Epidemic; Event; Family; Functional disorder; Future; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Engineering; Genetic Polymorphism; Genetic Population Study; Glucose; Goals; Hepatic; High Fat Diet; Homeostasis; Human; In Vitro; Inflammation; Inflammatory; Knock-out; Knockout Mice; Maintenance; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Peripheral Vascular Diseases; Pharmaceutical Preparations; Phenotype; Prevalence; Prevention; Regulation; Reporting; Research; Resources; Role; Signal Transduction; Stimulus; Stroke; Structure of beta Cell of islet; TXNIP gene; Testing; Transgenic Mice; Transgenic Organisms; United States; Vascular Endothelial Cell; Work; atherogenesis; base; cardiovascular disorder risk; cardiovascular risk factor; clinical practice; design; diabetes management; diabetic; diabetic patient; diabetogenic; early onset; in vivo; insight; lipid metabolism; maturity onset diabetes of the young; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; protective effect; risk minimization; transcription factor; western diet

PROJECT SUMMARY/ABSTRACT More than 29 million Americans, including children and adults, are living with diabetes and its prevalence is still on the rise in the United States. Cardiovascular diseases (CVD) are the primary cause of mortality among diabetic patients, accounting for almost 2 out of 3 deaths. In particular, diabetes aggravates the development of atherosclerosis, which is the usual cause of heart attack, stroke, and peripheral vascular diseases. Thus, minimization of the risk of CVD is a critical clinical goal in the management of diabetic patients. To date, no particular diabetes medication or combination of medications is considered superior to afford cardiovascular benefits. An increasing body of studies, including ours, uncovered evidence that KLF11 is a key factor in regulating glucose signaling in pancreatic β-cells and hepatic lipid metabolism. KLF11 gene polymorphisms are associated with human T2D. Indeed, KLF11 gene mutation causes MODY7, an early-onset T2D. However, the functions and detailed mechanisms of KLF11 in diabetes-associated cardiovascular complications remain largely unexploited. Our preliminary work identifies KLF11 as an anti-inflammatory factor in endothelial cells (EC) and here we present evidences that KLF11 is a glucose responsive gene, displays potent antioxidant and anti-inflammatory effects in EC in vitro and KLF11 deficiency aggravates diabetic atherosclerosis in vivo. Hence, we hypothesize that KLF11 protects the vasculature from atherogenesis by inhibiting endothelial cell oxidative stress through TXNIP, to be addressed by systematically implementing gain- and loss-of-KLF11 function strategies both in vitro and in vivo under diabetic and euglycemic conditions. First, we will define the role and molecular mechanisms of KLF11 in ECs oxidative stress in vitro (Aim 1). Next, leveraging our unique EC-specific KLF11 transgenic and knockout mouse models, available and specifically generated for this study, we will determine the role of KLF11 in the development of diet-induced atherosclerosis (Aim 2). Based on preliminary results and the field at large, we expect that KLF11 exerts protective effects in diabetes-associated atherosclerosis mainly through modulating redox genes, especially down-regulating thioredoxin interacting protein (TXNIP) in the presence of proatherogenic stimuli. This study will provide greater mechanistic insight into the overall KLF11 biology in the endothelium and, together with the new resources generated, will aid in future design of novel drugs to treat diabetes and associated CVD.

项目总结/摘要 超过2900万美国人，包括儿童和成人，患有糖尿病，其患病率仍然很高。 在美国呈上升趋势。心血管疾病（CVD）是死亡的主要原因， 糖尿病患者，几乎占死亡人数的三分之二。尤其是糖尿病会加速 动脉粥样硬化是心脏病发作、中风和外周血管疾病的常见原因。因此，在本发明中， CVD风险的最小化是糖尿病患者管理中的关键临床目标。至今没有 特定的糖尿病药物或药物组合被认为是上级的， 效益越来越多的研究，包括我们的研究，发现了KLF 11是一个关键因素的证据， 调节胰腺β细胞中的葡萄糖信号传导和肝脏脂质代谢。KLF 11基因多态性 与人类T2 D有关。事实上，KLF 11基因突变导致MODY 7，一种早发性T2 D。然而，在这方面， KLF 11在糖尿病相关心血管并发症中的功能和详细机制仍然存在 大部分未开发。我们的初步工作确定KLF 11作为内皮细胞中的抗炎因子 (EC)在这里，我们提出的证据表明，KLF 11是一个葡萄糖响应基因，显示出强大的抗氧化剂， 在体外EC中的抗炎作用和KLF 11缺陷在体内加重糖尿病动脉粥样硬化。 因此，我们假设KLF 11通过抑制内皮细胞增殖， 通过TXNIP的氧化应激，通过系统地实施KLF 11的获得和丧失来解决 在糖尿病和正常血糖条件下的体外和体内功能策略。首先，我们将定义 KLF 11在体外内皮细胞氧化应激中的作用及其分子机制（目的1）。接下来，利用我们独特的 EC特异性KLF 11转基因和基因敲除小鼠模型，可用于本研究并专门生成， 我们将确定KLF 11在饮食诱导的动脉粥样硬化发展中的作用（目的2）。基于 根据初步结果和整个领域，我们预计KLF 11在糖尿病相关性糖尿病中发挥保护作用。 动脉粥样硬化主要通过调节氧化还原基因，尤其是下调硫氧还蛋白相互作用 蛋白（TXNIP）在存在促动脉粥样硬化刺激。这项研究将提供更大的机制洞察力 进入内皮细胞中的整体KLF 11生物学，并与产生的新资源一起，将有助于 未来设计治疗糖尿病和相关CVD的新药。