Environmental Endocrine Disruption of Adipocyte Metabolism

描述（由申请人提供）：主要研究者罗伯特·萨吉斯博士致力于成为环境内分泌干扰、肥胖和代谢领域的独立研究者。特别是Sargis博士将研究环境污染物对脂肪细胞代谢和胰岛素信号传导的影响，以了解这些化合物导致肥胖和糖尿病流行的分子机制。植根于内分泌干扰物研究表明，化学污染物可以改变内分泌信号，“环境肥胖假说”假定合成化学品生产的指数增长和肥胖流行之间的因果关系。本申请的中心假设是环境内分泌干扰物对糖皮质激素受体活性的不适当调节将不利地影响脂肪细胞代谢和胰岛素信号传导。了解环境化学物质改变糖皮质激素受体激活的分子机制，可以大大提高我们对这些代谢紊乱的病理生理学的认识。初步数据表明，特定的内分泌干扰物激活糖皮质激素信号级联，刺激脂肪细胞分化，并诱导成熟脂肪细胞的胰岛素抵抗。为探讨环境内分泌干扰物在脂肪细胞代谢和胰岛素信号转导中的作用，本文拟开展以下研究：1）检测环境内分泌干扰物对成熟脂肪细胞胰岛素信号转导的影响，以确定这些化学物质的分子靶点; 2）确定糖皮质激素-类似的内分泌干扰物不适当地激活糖皮质激素受体，从而诱导胰岛素抗性;和3）表征由内分泌干扰物诱导的脂肪细胞基因表达的改变。总而言之，拟议的研究将极大地增强我们对环境内分泌干扰物在干扰脂肪细胞代谢中的作用的了解，这可能在一定程度上是肥胖和糖尿病祸害的根源。 拟议的项目将由Sargis博士在Matthew布雷迪博士和芝加哥大学内分泌、糖尿病和代谢科研究咨询委员会的指导下进行。Sargis的过渡到独立作为一个助理教授在这个5年的奖项完成。已经制定了一个职业发展计划，以帮助萨吉斯博士通过获得生物化学和分子生物学方面的新研究技能以及选定的课程来实现这一目标。总的来说，这些经验将扩大Sargis博士的知识基础，以便在分子代谢和环境健康的独特界面上进行这些前沿研究。芝加哥大学提供了一个丰富和充满活力的环境，在其中完成这个职业发展奖，和博士布雷迪，以及许多其他熟练的调查人员，是深深致力于帮助博士萨吉斯实现他的目标，成为一名独立的科学家。

DESCRIPTION (provided by applicant): Principal Investigator, Dr. Robert Sargis, endeavors to become an independent investigator at the interface of the fields of environmental endocrine disruption, obesity, and metabolism. In particular Dr. Sargis will examine the effects of environmental pollutants on adipocyte metabolism and insulin signaling in order to understand the molecular mechanisms by which these compounds contribute to the burgeoning obesity and diabetes epidemics. Rooted in endocrine disruptor research demonstrating that chemical pollutants can alter endocrine signaling, the "environmental obesogen hypothesis" posits a causative link between the exponential rise in synthetic chemical production and the obesity epidemic. The central hypothesis of this application is that inappropriate modulation of glucocorticoid receptor activity by environmental endocrine disruptors will adversely affect adipocyte metabolism and insulin signaling. Understanding the molecular mechanisms by which environmental chemicals alter glucocorticoid receptor activation could significantly advance our knowledge of the pathophysiology of these metabolic derangements. Preliminary data suggest that specific endocrine disruptors activate the glucocorticoid signaling cascade, stimulate adipocyte differentiation, and induce insulin resistance in the mature adipocyte. To investigate the role of environmental endocrine disruption in adipocyte metabolism and insulin signaling, the following studies are proposed: 1) to examine the effects of environmental endocrine disruptors on insulin signaling in mature adipocytes to identify the molecular targets of these chemicals; 2) to determine the mechanisms by which glucocorticoid-like endocrine disruptors inappropriately activate the glucocorticoid receptor and thereby induce insulin resistance; and 3) to characterize alterations in adipocyte gene expression induced by endocrine disruptors. In sum, the proposed studies will greatly enhance our understanding of the role of environmental endocrine disruptors in the perturbation of adipocyte metabolism that may in part underlie the scourges of obesity and diabetes. The proposed project will be conducted by Dr. Sargis under the guidance of Dr. Matthew Brady and a Research Advisory Committee in the Section of Endocrinology, Diabetes, and Metabolism at the University of Chicago. This application has been specifically designed to enable Dr. Sargis's transition to independence as an Assistant Professor at the completion of this 5-year award. A career development plan has been devised to help Dr. Sargis meet this goal through the acquisition of new research skills in biochemistry and molecular biology as well as selected coursework. Collectively, these experiences will expand Dr. Sargis's knowledge base in order to perform these cutting-edge studies at the unique interface of molecular metabolism and environmental health. The University of Chicago provides a rich and dynamic environment in which to complete this career development award, and Dr. Brady, as well as numerous other skilled investigators, is deeply committed to helping Dr. Sargis achieve his goal of becoming an independent scientist.