Regulation of Redox State by Txnip in Vascular Disease

应聘者描述(由申请人提供)：应聘者受过正规的医学和电气工程方面的培训，有过将机电原理应用于软骨和骨关节炎研究的研究经验。这项建议将允许候选人有一段辅导期来学习在心血管疾病中进行分子细胞生物学研究，并发展专注于定量了解血管疾病中细胞氧化还原信号网络的独立研究生涯。这项提案将重点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通过调节细胞氧化还原状态，抑制血管平滑肌细胞增殖，促进细胞凋亡。一个令人惊讶的新发现是，高葡萄糖浓度会强烈诱导TXNIP。由于有很好的证据表明，糖尿病血管疾病的部分原因是细胞氧化还原状态的失调，这导致了中心假说，即葡萄糖调节TXNIP会损害血管硫氧还蛋白的活性，导致糖尿病患者氧化应激增加，促进血管损伤。这项建议的目的是检验这样一种假设，即1)利用分子细胞生物学技术以及用于定量模拟TXNIP-硫氧还蛋白相互作用的活细胞成像方式，葡萄糖诱导TXNIP通过阻断硫氧还蛋白的抗氧化功能促进血管细胞中的促凋亡状态；以及2)TXNIP通过组织特异性靶向基因缺失调节糖尿病小鼠动脉的氧化还原状态。这些实验对于了解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，而糖尿病血管损伤是糖尿病患者发病率和死亡率的主要因素。糖尿病患者由于血管问题，心脏病发作和其他疾病的风险增加。原因尚不清楚，但其中一个原因是氧化导致细胞承受的压力增加。这项提案将研究一种细胞通常用来控制氧化应激的系统，并测试该系统是否会因血液中的高血糖水平而导致糖尿病细胞死亡。(摘要结束)

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)