Chloride channels in diabetic vascular disease

项目总结/摘要： 糖尿病仅在美国就影响约2300万人，其中最普遍的形式是糖尿病。 2型糖尿病（T2 D）占诊断病例的约90%。肥胖， 缺乏身体活动加上遗传易感性与以下疾病的患病率上升有关： 2型糖尿病糖尿病患者心血管疾病（CVD）的风险增加3倍，并涉及多个 这些因素包括高血糖、胰岛素抵抗和血脂异常。外周动脉疾病 (PAD)通常发生在糖尿病中，表现为下肢动脉闭塞性疾病， 四肢PAD通常表明预后不良，因为它表明更广泛的CVD风险 特别是涉及脑血管、冠状动脉和肾血管系统。 血管平滑肌细胞（肌细胞）膜电位是血管平滑肌细胞（肌细胞）的主要调节因子。 动脉收缩性糖尿病可以改变细胞内几种离子通道的表达和活性， 与细胞内钙（Ca 2+）信号传导相关的血管。跨膜 蛋白质16 A（TMEM 16 A，Anoctamin 1，ANO 1）通道是Ca 2+激活的氯离子（Cl−） 在动脉肌细胞中表达并触发Cl-流出、肌细胞膜 去极化和血管收缩。动脉肌细胞离子通道基因表达与 由几种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影响通道表达并诱导血管生成。 糖尿病的功能障碍。动脉肌细胞ANO 1在糖尿病发病中的作用 尚未研究血管功能障碍。这个应用程序源于新颖和令人兴奋的 调节动脉肌细胞中Ano 1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ANO 1表达、ANO 1电流和血管收缩。的目标 该建议是鉴定介导Ano 1表达的关键蛋白和信号机制， 阻力动脉，并测试新化合物在缓解糖尿病方面的治疗潜力- 引起血管收缩。

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.