Chloride channels in diabetic vascular disease

项目摘要/摘要： 仅在美国就有约2300万人受到糖尿病的影响，这种疾病是最常见的 疾病为2型糖尿病(T2D)，占确诊病例的90%。肥胖， 缺乏体力活动加上遗传易感性与高血压患病率上升有关 T2D。患心血管疾病(CVD)的风险在糖尿病患者中增加3倍，涉及几个 因素，包括高血糖、胰岛素抵抗和血脂异常。外周动脉疾病 (PAD)常见于糖尿病，表现为下肢动脉闭塞性病变。 四肢。PAD通常提示预后不良，因为它预示着更大的心血管疾病风险。 尤其是累及脑血管、冠状动脉和肾血管系统。 血管平滑肌细胞(肌细胞)膜电位是一种主要的调节因子 动脉的收缩能力。糖尿病可改变血管内皮细胞几种离子通道的表达和活性 与细胞内钙信号有关的血管系统。跨膜 蛋白16A(TMEM16A，AnocTamin1，ANO1)通道是钙激活的氯(Cl−)通道。 在动脉肌细胞中表达并触发氯离子外流的通道，心肌细胞膜 去极化和血管收缩。动脉肌细胞离子通道基因表达密切相关 受多种转录因子介导的信号机制的调节。病态的 这些调节机制的改变可能会影响通道表达并诱导血管 糖尿病中的功能障碍。动脉肌细胞ANO1在糖尿病发生发展中的作用 血管功能障碍尚未得到研究。这一应用源于新颖和令人兴奋的 调控动脉肌细胞Ano1表达的特定信号机制的数据 控制动脉的收缩能力。糖尿病引起的这些信号通路的失调导致 动脉肌细胞ANO1表达增加，ANO1电流和血管收缩增加。的目标是 本研究旨在确定Ano1基因表达的关键蛋白和信号传导机制。 阻力动脉和测试新化合物在缓解糖尿病方面的治疗潜力- 诱导血管收缩。

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.