SIRT6 and vascular endothelial homeostasis

SIRT6 与血管内皮稳态

• 批准号: 9380604
• 负责人: ZHENG-GEN JIN
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF ROCHESTER
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9380604
• 关键词: Address; Antioxidants; Apolipoprotein E; Apoptosis; Atherosclerosis; Biological; Blood Vessels; Cardiovascular system; Cell Aging; ChIP-seq; Chronic; DNA Damage; Development; Diabetes Mellitus; Diabetic mouse; Endothelial Cells; Endothelium; Epidemic; Epigenetic Process; Family member; Gene Cluster; Gene Expression; Genetic Transcription; Genome Stability; Glucose; Goals; High Prevalence; Homeostasis; Human; Hyperglycemia; Impairment; In Vitro; Individual; Inflammation; Knock-out; Link; Longevity; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Molecular; Morbidity - disease rate; Mus; NADPH Oxidase; NOS3 gene; Nitric Oxide; Obesity; Pathogenesis; Pathologic; Pathway interactions; Physiological; Play; Predisposition; Protein Family; Reactive Oxygen Species; Regulation; Research; Resort; Role; SIRT1 gene; Scheme; Signal Transduction; Sirtuins; Small Interfering RNA; Stress; Technology; Testing; Transgenes; United States; Vasodilation; diabetic; endothelial dysfunction; experimental study; fighting; gain of function; improved; in vivo; insight; knock-down; loss of function; member; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; overexpression; premature; prevent; protective effect; public health relevance; resistance gene; therapeutic candidate; transcriptome sequencing; vascular endothelial dysfunction

The major goal of the project is to elucidate the molecular mechanism underlying diabetes-associated vascular endothelial dysfunction. Diabetes mellitus, one of the major leading chronic morbidities worldwide, is continually increasing with a high prevalence in the United States and throughout the world. Cardiovascular complications are mainly responsible for the high morbidity and mortality in people with diabetes. Vascular endothelial dysfunction in diabetes mellitus critically contributes to the pathogenesis of atherosclerotic disease and its cardiovascular complications. However, the exact molecular mechanisms of endothelial dysfunction in diabetes remain largely unknown. SIRT6, a new member of the sirtuin family of proteins, has recently recognized as a master regulator of stress resistance, gene transcription, genome stability and metabolic homeostasis. SIRT6 has distinct cellular localization and function from other sirtuin family members such as well-studied SIRT1. Recent studies indicate that SIRT6 deficiency is associated with metabolic disease, and SIRT6 has been proposed as a potential therapeutic candidate fighting the metabolic syndrome epidemic. In parallel, emerging evidence from our group suggests that SIRT6 plays a crucial role in regulation of endothelial homeostasis and endothelial SIRT6 deficiency is associated with diabetes. As such we propose that an alternation of SIRT6 expression in diabetes could result in endothelial dysfunction and thus a predisposition to atherosclerosis, and resorting SIRT6 function could improve endothelial homeostasis and protects against atherosclerosis in diabetes. We will use the combination of in vitro and in vivo experiments to test this novel hypothesis. Results from our proposed studies, if as anticipated, would help to understand the molecular basis of endothelial dysfunction, and facilitate the development of new therapeutic approaches, such as enhancing SIRT6 expression and activity, to limit diabetes-accelerated atherosclerotic cardiovascular diseases.

该项目的主要目标是阐明潜在的分子机制。 糖尿病相关的血管内皮功能障碍。糖尿病，一种 在全球范围内，主要的慢性病正在以较高的速度持续增加 在美国和全世界都很流行。心血管并发症 是糖尿病患者高发病率和高死亡率的主要原因。 糖尿病患者血管内皮功能障碍是导致血管内皮功能障碍的重要因素。 动脉粥样硬化性疾病及其心血管并发症的发病机制。然而， 糖尿病血管内皮细胞功能障碍的确切分子机制在很大程度上仍然存在。 未知。SIRT6是sirtuin蛋白家族的一个新成员，最近发现 作为抗逆性、基因转录、基因组稳定性和 代谢动态平衡。SIRT6具有不同于其他基因的细胞定位和功能 Sirtuin家族成员等研究得很好的SIRT1。最近的研究表明，SIRT6 缺乏与代谢性疾病有关，SIRT6已被认为是一种 与代谢综合征流行病作斗争的潜在治疗候选人。同时， 来自我们小组的新证据表明，SIRT6在调控中发挥着关键作用 内皮细胞动态平衡和内皮细胞SIRT6缺陷与糖尿病相关。 因此，我们认为在糖尿病中SIRT6表达的改变可能导致 内皮功能障碍和动脉粥样硬化的易感性，并求助于SIRT6 功能可改善血管内皮细胞动态平衡，保护动脉粥样硬化 糖尿病。我们将使用体外和体内实验相结合的方法来验证这一点 新奇的假设。我们建议的研究结果，如果如预期，将有助于 了解内皮功能障碍的分子基础，并促进 开发新的治疗方法，如增强SIRT6的表达和 活动，以限制糖尿病加速的动脉粥样硬化性心血管疾病。