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：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)确定通过FoxOI叉头转录因子在脂肪代谢调节中发出信号的生理相关机制。首席研究员是一位接受过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作为独立调查员取得成功所需的研究技能。 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在胰岛素作用中发挥着关键作用。然而，它的信号机制仍然只有部分了解。这项建议研究了FoxOI在脂肪组织生理学中的作用。这项工作对于理解糖尿病和超重/肥胖中胰岛素抵抗的异常信号事件特别相关。在美国，影响65%的成年人和16.5%的儿童的疾病是糖尿病和超重/肥胖。受训人员假设FoxOI对脂肪细胞中的胰岛素活动进行负面调节，其效果可能至少部分地由PPAR伽马介导的信号变化来解释。其具体目的包括：1)用腺病毒在培养的脂肪细胞中表达野生型和突变型FoxOI转基因基因，以确定它们对胰岛素作用的影响，并寻找依赖FoxOI转录的新靶点；2)通过对FoxOI和FOXO4基因敲除小鼠的分析，研究FoxO蛋白在体内的作用；以及3)利用脂肪靶向突变的FoxOI建立新的体内模型。这些研究将首次使用体外和体内互补的方法全面研究FoxOI在脂肪组织中的生理作用。 杰罗尔德·奥列夫斯基博士将在加州大学圣地亚哥分校担任金博士科学发展的导师，他的实验室将为金博士提供一个异常多样化的智力和研究环境。Olefsky博士被公认为是胰岛素作用和糖尿病领域的杰出导师和领导者。这种方法将为金医生提供一个坚实的平台，以构建一个成功的职业生涯，成为一名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.