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

描述(由申请人提供)： 这份建议详细说明了我在学术心血管医学领域的职业发展的5年综合培训计划。我已经在布里格姆和妇女医院完成了心血管医学的临床培训，并计划开始一项有指导的研究计划，为独立的生物医学研究生涯提供必要的额外科学培训。我将在细胞生物学、遗传学、分子生物化学、新陈代谢和体内生理学方面获得深入的经验，如应用于葡萄糖代谢的氧化还原调节。理查德·T·李博士将指导我的科学和职业发展。李博士在氧化还原调节、机械转导和心血管疾病领域是国际公认的领导者，并在学术医学和基础科学领域拥有成功的职业指导记录。贝丝·伊斯雷尔女执事医院的埃文·罗森博士是新陈代谢和异糖作用方面的专家，他将担任共同导师。此外，一个由资深医学科学家(Peter Libby博士、Thomas Michel博士)组成的咨询委员会将提供科学和职业建议。这一提议的中心假设是，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调节因子。TXNIP的表达是高度葡萄糖和胰岛素反应的。我的研究表明，强制表达TXNIP显著降低了小鼠的葡萄糖摄取，靶向TXNIP基因缺失促进了葡萄糖的摄取，并钝化了肝脏葡萄糖的产生。我的目标是：1)利用基因缺失和脂肪细胞强制过表达技术，探讨TXNIP调节外周组织(脂肪)葡萄糖摄取的机制；2)利用脂肪选择性靶向TXNIP基因缺失的小鼠，测试外周葡萄糖摄取受TXNIP表达调控的假说；以及3)使用TXNIP基因缺失小鼠定义的氧化应激模型，测试TXNIP介导的葡萄糖摄取障碍的假说。相关性：糖尿病是一种在全球范围内不断扩大的流行病，每15名成年人中就有1人受到影响。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，最终目的是找到预防或治疗这种毁灭性疾病及其心血管后果的新疗法。(摘要结束)

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)