Regulation of Redox State by Txnip in Vascular Disease

Txnip 在血管疾病中对氧化还原状态的调节

• 批准号: 7623897
• 负责人: Parth Patwari
• 金额: $ 15.23万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623897
• 关键词: Abbreviations; Antioxidants; Apoptosis; Apoptotic; Arteries; Binding; Blood; Blood Vessels; Cardiovascular Diseases; Cartilage; Cause of Death; Cell Survival; Cells; Cellular biology; Cholecalciferol; Data; Defect; Degenerative polyarthritis; Diabetes Mellitus; Diabetic Angiopathies; Disease; Disulfides; Dithiothreitol; Electrical Engineering; Endothelial Cells; Environment; Event; Fluorescence; Fluorescence Resonance Energy Transfer; Functional disorder; Gene Deletion; Genes; Glucose; Glutathione; Growth Factor; Hypoglycemia; Image; In Vitro; Injury; Investigation; Knockout Mice; Learning; Life; MAP3K5 gene; Mediating; Medicine; Mentors; Metabolic; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Orphan; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Participant; Pathway interactions; Platelet-Derived Growth Factor; Proteins; Reactive Oxygen Species; Regulation; Reporting; Research; Research Personnel; Risk; Role; Signal Transduction; Spectrum Analysis; Staging; Stress; Stress Tests; Sulfhydryl Compounds; System; Techniques; Testing; Thioredoxin; Tissues; Training; Translational Research; Vascular Diseases; abstracting; blood glucose regulation; career; cell growth; cellular imaging; design; diabetic; diabetic patient; experience; imaging modality; in vivo; inhibitor/antagonist; interdisciplinary approach; mortality; mouse model; overexpression; oxidation; programs; research study; response; vascular smooth muscle cell proliferation

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)

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。该提案将使候选人有一段指导时间来学习进行心血管疾病的分子细胞生物学研究，并发展专注于血管疾病细胞氧化还原信号网络的定量理解的独立研究生涯。该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 已被证明可以通过控制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 受到高葡萄糖浓度的强烈诱导。由于有充分的证据表明糖尿病血管疾病部分是由细胞氧化还原状态失调引起的，这导致了一个中心假设：葡萄糖对 Txnip 的调节会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。本提案的目的是检验以下假设：1) 使用分子细胞生物学技术以及活细胞成像方式对 Txnip-硫氧还蛋白相互作用进行定量建模，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的促凋亡状态； 2) Txnip 使用组织特异性靶向基因删除来调节小鼠糖尿病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基本途径，而糖尿病血管损伤是糖尿病患者发病和死亡的主要原因。由于血管问题，糖尿病患者患心脏病和其他疾病的风险增加。原因尚不清楚，但原因之一是氧化导致细胞压力增加。该提案将研究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葡萄糖水平而导致糖尿病细胞死亡。 （摘要完）