Thioredoxin Interacting Protein's (Txnip) Role in Glucose Metaboism in Fat

硫氧还蛋白相互作用蛋白 (Txnip) 在脂肪中葡萄糖代谢中的作用

• 批准号: 7762845
• 负责人: WILLIAM A CHUTKOW
• 金额: $ 13.64万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762845
• 关键词: Adipocytes; Adult; Advisory Committees; Affect; Antioxidants; Attenuated; Basic Science; Binding; Biochemistry; Biology; Cardiovascular Diseases; Cardiovascular system; Cells; Cellular biology; Clinical; Cysteine; Data; Defect; Development; Diabetes Mellitus; Disease; Disulfides; Enzymes; Epidemic; Event; Fatty acid glycerol esters; Ferredoxin; Gene Deletion; Genes; Glucose; Glutathione; Goals; Hepatic; Hospital Planning; Hospitals; Hypertriglyceridemia; Hypoglycemia; Impairment; Insulin; Insulin Resistance; Knockout Mice; Light; Liver; Mammalian Cell; Mediating; Mediator of activation protein; Medical; Medicine; Mentors; Mentorship; Metabolic; Metabolism; Modeling; Molecular Genetics; Mouse Strains; Mus; Mutation; Operating System; Oxidation-Reduction; Oxidative Stress; Peripheral; Physiology; Plants; Play; Postabsorptive Hypoglycemia; Process; Proteins; Regulation; Reporting; Research; Research Personnel; Role; Scientist; Signal Transduction; Signaling Molecule; Sulfhydryl Compounds; Techniques; Testing; Thioredoxin; Tissues; Training; Training Programs; Woman; abstracting; basal insulin; base; blood glucose regulation; career; career development; diabetic patient; experience; genetic regulatory protein; glucose metabolism; glucose production; glucose transport; glucose uptake; in vivo; inhibitor/antagonist; insulin signaling; overexpression; prevent; programs; protein protein interaction; response; sugar; tool; transcription factor

DESCRIPTION (provided by applicant): This proposal details a comprehensive 5-year training program for my career development in academic cardiovascular medicine. I have completed clinical training in cardiovascular medicine at Brigham and Women's Hospital and plan to embark on a mentored research program to provide additional scientific training necessary for an independent career in biomedical resesarch. I will gain in-depth experience in cellular biology, genetics, molecular biochemistry, metabolism, and in vivo physiology as applied to the redox regulation of glucose metabolism. Dr. Richard T. Lee will mentor my scientific and career development. Dr. Lee is an internationally recognized leader in the fields of redox regulation, mechano-transduction, and cardiovascular diseases, and has a proven track record for successful career mentorship in academic medicine and the basic sciences. Dr. Evan Rosen of Beth Isreal Deaconess Hospital, an expert in metabolic metabolism and isulin-action, will serve as a co-mentor. In addition, an advisory committee of established medical scientists (Drs. Peter Libby, Thomas Michel) will provide scientific and career advice. The central hypothesis of this proposal is that the ubiquitously expressed redox regulatory protein Txnip (thioredoxin interacting protein) is a key mediator of glucose homeostasis. Txnip expression is highly glucose and insulin responsive. I show that forced Txnip expression significantly attenuates glucose uptake, and targeted Txnip gene deletion in mice promotes glucose uptake and blunts liver glucose production. My aims are: 1) To explore the mechanisms by which Txnip regulates glucose uptake in a peripheral tissue (fat), using gene deletion and forced overexpression techniques in adipocytes; 2) To test the hypothesis that peripheral glucose uptake is regulated by Txnip expression in fat using mice with fat-selective targeted Txnip gene deletion; and 3) To test the hypothesis that impairment of glucose uptake by oxidative stress is mediated by Txnip using well-defined models of oxidative stress as applied to Txnip gene-deleted mice. Relevance: Diabetes mellitus is an expanding worldwide epidemic that already affects greater than 1 in 15 adults. 4 out of 5 diabetic patients will die prematurely from a cardiovascular cause. This research aims to understand the fundamental mechanisms of dysregulated sugar metabolism with the ultimate goal of discovering new therapies to prevent or treat this devastating disease and its cardiovascular consequences. (End of Abstract)

描述（由申请人提供）： 这份提案详细说明了一个全面的5年培训计划，为我的职业发展，在学术心血管医学。我已经在布里格姆妇女医院完成了心血管医学的临床培训，并计划开展一项指导研究计划，为生物医学研究的独立职业提供必要的额外科学培训。我将获得细胞生物学，遗传学，分子生物化学，代谢和体内生理学的深入经验，适用于葡萄糖代谢的氧化还原调节。Richard T.李将指导我的科学和职业发展。李博士是国际公认的氧化还原调节，机械转导和心血管疾病领域的领导者，并在学术医学和基础科学方面拥有成功的职业指导记录。贝丝以色列女执事医院的埃文罗森博士是代谢代谢和胰岛素作用方面的专家，他将担任共同导师。此外，一个由知名医学科学家（彼得·利比博士、托马斯·米歇尔博士）组成的咨询委员会将提供科学和职业建议。这个提议的中心假设是，普遍表达的氧化还原调节蛋白Txnip（硫氧还蛋白相互作用蛋白）是葡萄糖稳态的关键介质。Txnip表达是高度葡萄糖和胰岛素响应性的。我表明，强制Txnip表达显着减弱葡萄糖摄取，并在小鼠中有针对性的Txnip基因缺失促进葡萄糖摄取和钝化肝脏葡萄糖的生产。我的目标是：1）使用脂肪细胞中的基因缺失和强制过表达技术来探索Txnip调节外周组织（脂肪）中葡萄糖摄取的机制; 2）使用具有脂肪选择性靶向Txnip基因缺失的小鼠来检验外周葡萄糖摄取受脂肪中Txnip表达调节的假设;和3）使用应用于Txnip基因缺失小鼠的明确定义的氧化应激模型来检验由氧化应激引起的葡萄糖摄取受损由Txnip介导的假设。相关性：糖尿病是一种正在扩大的全球流行病，已经影响超过1/15的成年人。五分之四的糖尿病患者会因心血管原因过早死亡。这项研究旨在了解糖代谢失调的基本机制，最终目标是发现新的疗法来预防或治疗这种毁灭性的疾病及其心血管后果。 (End摘要）