Regulation of Redox State by Txnip in Vascular Disease

描述（由申请人提供）：候选人接受过医学和电气工程方面的正式培训，具有将机电学原理应用于软骨和骨关节炎研究的先前研究经验。该提案将允许候选人有一个指导期，学习进行心血管疾病的分子细胞生物学研究，并发展独立的研究生涯，重点是定量了解血管疾病中的细胞氧化还原信号网络。该提案将集中于了解硫氧还蛋白相互作用蛋白（Txnip）在糖尿病血管疾病中的作用，该蛋白结合并抑制硫氧还蛋白。Txnip已显示通过操纵细胞氧化还原状态来抑制血管平滑肌细胞增殖并促进细胞凋亡。一个令人惊讶的新发现是Txnip是由高葡萄糖浓度强烈诱导的。由于有很好的证据表明糖尿病血管疾病部分是由细胞氧化还原状态的失调引起的，这导致了核心假设，即葡萄糖对Txnip的调节损害血管硫氧还蛋白活性，导致氧化应激增加并促进糖尿病中的血管损伤。该提议的目的是检验以下假设：1）通过阻断硫氧还蛋白的抗氧化功能，葡萄糖诱导Txnip促进血管细胞中的促凋亡状态，使用分子细胞生物学技术以及活细胞成像模式对Txnip-硫氧还蛋白相互作用进行定量建模;和2）Txnip通过组织特异性靶向基因缺失调节小鼠糖尿病动脉中的氧化还原状态。这些实验对于理解Txnip和硫氧还蛋白在血管疾病中的作用至关重要，并可能揭示糖尿病血管损伤的新的基本途径，这是糖尿病患者发病率和死亡率的主要原因。糖尿病患者由于血管问题而增加了心脏病发作和其他疾病的风险。原因尚不清楚，但其中一个原因是由于氧化而增加了细胞的压力。该提案将研究细胞通常用于控制氧化应激的系统，并测试该系统是否会由于血液中的高葡萄糖水平而导致糖尿病细胞死亡。(End摘要）

DESCRIPTION (provided by applicant): The candidate is formally trained in medicine and electrical engineering with prior research experience that has applied principles of electromechanics to investigations of cartilage and osteoarthritis. This proposal will allow the candidate a mentored period to learn to conduct molecular cell biology research in cardiovascular disease and develop an independent research career focused on quantitative understanding of cellular redox signaling networks in vascular disease. This proposal will focus on understanding the role of thioredoxin interacting protein (Txnip), which binds and inhibits thioredoxin, in diabetic vascular disease. Txnip has been shown to inhibit vascular smooth muscle cell proliferation and promote apoptosis by manipulation of the cellular redox state. A surprising new finding is that Txnip is strongly induced by high glucose concentrations. Since there is good evidence that diabetic vascular disease is caused in part by dysregulation of the cellular redox state, this has led to the central hypothesis that the regulation of Txnip by glucose impairs vascular thioredoxin activity, leading to increased oxidative stress and promoting vascular injury in diabetes. The aims of this proposal are to test the hypothesis that 1) the induction of Txnip by glucose promotes a pro- apoptotic state in vascular cells through blockade of thioredoxin's antioxidant function, using molecular cell biology techniques as well as live-cell imaging modalities for quantitative modeling of the Txnip-thioredoxin interaction; and 2) Txnip regulates redox state in diabetic arteries in mice, using tissue-specific targeted gene deletion. These experiments are critical for understanding Txnip and thioredoxin's roles in vascular disease and may reveal a new fundamental pathway for diabetic vascular injury, which is a major contributor to morbidity and mortality in diabetic patients. People with diabetes have an increased risk of heart attack and other diseases due to problems with their blood vessels. The reasons are not clear but one reason is increased stress on the cells due to oxidation. This proposal will study a system the cells normally use to control oxidative stress and test whether this system could cause the death of cells in diabetes due to the high glucose levels in the blood. (End of Abstract)