Chloride channels in diabetic vascular disease

糖尿病血管疾病中的氯离子通道

• 批准号: 10063958
• 负责人: M. Dennis Marcus Leo
• 金额: $ 38万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063958
• 关键词: Affect; Animals; Arterial Occlusive Diseases; Arteries; Biological Assay; Biotinylation; Blood Vessels; Blood flow; Calcium; Cardiovascular Diseases; Cells; Chloride Channels; Chlorides; Co-Immunoprecipitations; Coronary; Coupled; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Diagnosis; Disease; Dyslipidemias; Economics; Electrophoretic Mobility Shift Assay; Electrophysiology (science); Enzymes; Factor Analysis; Gene Expression; Genes; Genetic Predisposition to Disease; Genetic Transcription; Goals; Hyperglycemia; Immunofluorescence Immunologic; Incidence; Insulin; Insulin Resistance; Integral Membrane Protein; Ion Channel; Knockout Mice; Lead; Lower Extremity; Luciferases; Mediating; Medicine; Membrane; Membrane Potentials; Messenger RNA; Metabolic; Morbidity - disease rate; Muscle Cells; Myography; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organ; Oxygen; Pathologic; Patients; Peripheral arterial disease; Prevalence; Prognosis; Proteins; Public Health; Repressor Proteins; Research Proposals; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Snails; Surface; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Transcription Repressor; Vascular Diseases; Vascular Smooth Muscle; Vasodilation; Western Blotting; cardiovascular disorder risk; cerebrovascular; chromatin immunoprecipitation; chromosome conformation capture; diabetic; diabetic cardiomyopathy; glycogen synthase kinase 3 beta inhibitor; in vivo; kidney vascular structure; mortality; non-diabetic; novel; patch clamp; physical inactivity; pressure; promoter; social; stem; targeted treatment; therapeutic evaluation; transcription factor; vasoconstriction; voltage

PROJECT SUMMARY/ABSTRACT: Diabetes affects ~23 million people in the US alone with the most prevalent form of the disease being type-2 diabetes (T2D), which accounts for ~90%, of diagnosed cases. Obesity, physical inactivity coupled with genetic susceptibility is associated with the rising prevalence of T2D. The risk of cardiovascular disease (CVD) increases 3-fold in diabetes and involves several factors, including hyperglycemia, insulin resistance and dyslipidemia. Peripheral artery disease (PAD) commonly occurs in diabetes and manifests as occlusive arterial disease of the lower extremities. PAD generally points to poor prognosis because it is indicative of wider CVD risk especially involving the cerebrovascular, coronary and renovascular systems. Vascular smooth muscle cell (myocyte) membrane potential is a major regulator of arterial contractility. Diabetes can alter the expression and activity of several ion channels in the vasculature that are associated with intracellular calcium (Ca2+) signaling. Transmembrane protein 16A (TMEM16A, Anoctamin1, ANO1) channels are Ca2+-activated chloride (Cl−) channels that are expressed in arterial myocytes and triggers Cl- efflux, myocyte membrane depolarization and vasoconstriction. Arterial myocyte ion channel gene expression is tightly regulated by signaling mechanisms mediated by several transcription factors. A pathological alteration in these regulatory mechanisms may affect channel expression and induce vascular dysfunction in diabetes. The role of arterial myocyte ANO1 in the development of diabetic vascular dysfunction has not been investigated. This application stems from novel and exciting data of specific signaling mechanisms that regulate Ano1 expression in arterial myocytes to control arterial contractility. Diabetes-induced dysregulation of these signaling pathways leads to increased arterial myocyte ANO1 expression, ANO1 currents and vasoconstriction. The goal of this proposal is to identify key proteins and signaling mechanisms mediating Ano1 expression in resistance arteries and test the therapeutic potential of novel compounds in alleviating diabetes- induced vasoconstriction.

项目摘要/摘要： 仅在美国，糖尿病就会以最普遍的形式影响约2300万人 疾病是2型糖尿病（T2D），占诊断病例约为90％的疾病。肥胖， 身体不活跃以及遗传敏感性与升高的患病率上升有关 T2D。心血管疾病（CVD）的风险在糖尿病中增加了3倍，涉及几种 因素，包括高血糖，胰岛素抵抗和血脂异常。周围动脉疾病 （PAD）通常发生在糖尿病中，表现为较低的闭塞动脉疾病 四肢。垫通常表明预后不良，因为它表明CVD风险更大 特别涉及脑血管，冠状动脉和肾血管系统。 血管平滑肌细胞（肌细胞）膜电位是主要调节剂 动脉收缩。糖尿病可以改变几个离子通道的表达和活性 与细胞内钙（CA2+）信号传导相关的脉管系统。跨膜 蛋白16A（TMEM16A，ANOCTAMIN1，ANO1）通道是Ca2+活化的氯化物（CL-） 在动脉心肌细胞和触发cl-外排，心肌细胞膜中表达的通道 去极和血管收缩。动脉肌细胞离子通道基因表达紧密 由由几个转录因子介导的信号传导机制调节。病理 这些调节机制的改变可能会影响通道表达并诱导血管 糖尿病功能障碍。动脉肌细胞ANO1在糖尿病发展中的作用 尚未研究血管功能障碍。该应用程序从小说和令人兴奋的 调节动脉肌细胞中ANO1表达的特定信号传导机制的数据 控制动脉收缩。糖尿病引起的这些信号通路的失调导致 增加动脉肌细胞ANO1表达，ANO1电流和血管收缩。目标 该建议是确定介导ANO1表达的关键蛋白质和信号传导机制 耐药性动脉并测试新化合物在减轻糖尿病中的治疗潜力 - 引起血管收缩。