Studies of Fox01 in Insulin Resistance and its interaction with PPARgamma

描述（由申请人提供）： 拟议培训的目标有两个方面：i）提供培训和指导，为Jane Kim博士在糖尿病和胰岛素作用方面的独立研究生涯做好准备; ii）通过FoxOI叉头转录因子在脂肪代谢调节中识别生理相关的信号传导机制。主要研究者是一名NIH培训的儿科内分泌学家，他还在纽约哥伦比亚大学完成了基础科学研究奖学金。拟议的资助期将使她能够充分发展必要的研究技能，成功地作为一个独立的调查。 来自脊椎动物和无脊椎动物模型的遗传和生化证据表明FoxOI在胰岛素作用中起关键作用。然而，其信号传导机制仍然只有部分了解。该提案研究了FoxOI在脂肪组织生理学中的作用。这项工作是特别相关的理解异常信号传导事件的基础胰岛素抵抗的糖尿病和超重/肥胖症，疾病影响65%的成年人和16.5%的儿童在美国的培训生假设，FoxOI负调节胰岛素的作用在脂肪细胞和它的效果可以解释，至少部分，通过改变PPARgamma介导的信号。具体目标包括：1）在培养的脂肪细胞中使用野生型和突变型FoxOI转基因的腺病毒表达，以确定它们对胰岛素作用的影响，并鉴定FoxOI依赖性转录的新靶点; 2）通过FoxOI和FoxO 4敲除小鼠的分析研究FoxO蛋白的体内作用;和3）产生具有FoxOI的脂肪靶向突变的新体内模型。这些研究将是第一个全面调查的FoxOI在脂肪组织中的生理作用，使用互补的体外和体内的方法。 博士Jerrold Olefsky将在加州大学圣地亚哥分校担任Kim博士科学发展的导师，他的实验室将为Kim博士提供一个非常多样化的知识和研究环境。Olefsky博士被公认为胰岛素作用和糖尿病领域的杰出导师和领导者。这种方法将为Kim博士提供一个坚实的平台，以建立一个成功的职业生涯，作为一个独立的科学家和学术儿科内分泌学家。

DESCRIPTION (provided by applicant): The goals of the proposed training are two-fold: i) to provide training and mentoring to prepare Dr. Jane Kim for an independent research career in diabetes and insulin action and ii) to identify physiologically relevant mechanisms of signaling via the FoxOI forkhead transcription factor in the regulation of adipose metabolism. The principal investigator is a NIH-trained pediatric endocrinologist who has also completed a basic science research fellowship at Columbia University, NY. The proposed funding period will enable her to fully develop the research skills necessary to succeed as an independent investigator. Genetic and biochemical evidence from both vertebrate and invertebrate models indicate that FoxOI plays a pivotal role in insulin action. However, its signaling mechanism remains only partially understood. This proposal investigates the role of FoxOI in adipose tissue physiology. This work is particularly relevant to understanding the aberrant signaling events that underlie insulin resistance in diabetes and overweight/obesity, diseases that affect 65% of adults and 16.5% of children in the U.S. The trainee hypothesizes that FoxOI negatively regulates insulin action in adipocytes and that its effect may be explained, at least in part, by the alterations in PPARgamma-mediated signaling. The specific aims include: 1) using adenoviral expression of wild-type and mutant FoxOI transgenes in cultured adipocytes to define their effects on insulin action and to identify novel targets of FoxOI-dependent transcription; 2) investigating the in vivo role of FoxO proteins through the analysis of FoxOI and FoxO4 knockout mice; and 3) generating novel in vivo models with adipose-targeted mutations of FoxOI. These studies will be the first to comprehensively investigate the physiologic role of FoxOI in adipose tissue using complementary in vitro and in vivo approaches. Dr. Jerrold Olefsky will serve as a mentor for Dr. Kim's scientific development at the University of California, San Diego, and his laboratory will provide Dr. Kim with access to an exceptionally diverse intellectual and research environment. Dr. Olefsky is recognized as an outstanding mentor and leader in the field of insulin action and diabetes. This approach will provide Dr. Kim with a solid platform to construct a successful career as an independent scientist and academic pediatric endocrinologist.