Environmental Endocrine Disruption of Adipocyte Metabolism

环境内分泌对脂肪细胞代谢的干扰

• 批准号: 8265337
• 负责人: Robert M Sargis
• 金额: $ 16.02万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265337
• 关键词: Acute; Adipocytes; Adipose tissue; Advisory Committees; Affect; Animals; Attention; Award; Biochemical; Biochemistry; Biological Assay; Chemical Actions; Chemicals; Chicago; Chronic; Commit; Complex; Data; Development; Development Plans; Diabetes Mellitus; Disease; Dose; Dyslipidemias; Endocrine; Endocrine Disruptors; Endocrine Glands; Endocrine disruption; Endocrinology; Energy Metabolism; Environment; Environmental Health; Environmental Pollutants; Epidemic; Epidemiology; Foundations; Functional disorder; Gene Expression; Gene Expression Profiling; Gene Proteins; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Gonadal Steroid Hormones; Healthcare Systems; Hormones; Human; Individual; Insulin Resistance; K-Series Research Career Programs; Kinetics; Knowledge; Ligands; Link; Lipids; Measurement; Mediating; Metabolic; Metabolism; Molecular; Molecular Biology; Molecular Profiling; Molecular Target; Morphology; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Hormone Receptors; Obesity; Pathway interactions; Physiology; Plant Roots; Population; Prevalence; Principal Investigator; Production; Public Policy; Receptor Activation; Receptor Signaling; Regulation; Relative (related person); Reporter; Research; Research Personnel; Response Elements; Role; Scheme; Scientist; Scourge; Signal Transduction; Sum; Testing; Thyroid Gland; Time; Tissues; Translations; Universities; Work; adipocyte differentiation; bioaccumulation; career development; clinically significant; cofactor; defined contribution; design; environmental chemical; experience; glucocorticoid-induced orphan receptor; human data; in vivo; insight; insulin sensitivity; insulin signaling; knowledge base; meetings; novel; pollutant; professor; public health relevance; receptor; receptor binding; research study; response; skills; sound; tool

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. PUBLIC HEALTH RELEVANCE: The burgeoning obesity and diabetes epidemics are placing enormous strains on our healthcare system; however, the precise factors responsible for these diseases are incompletely understood. The proposed studies will characterize the molecular mechanisms by which environmental endocrine disrupting chemicals contribute to the development of obesity and diabetes through disruption of adipocyte metabolism and insulin signaling with particular focus on alterations in glucocorticoid signaling. Understanding the potential contribution of environmental pollutants to the development of obesity and diabetes will provide the scientific foundation upon which to develop sound public policy directed at mitigating the effects of environmental depredation on the metabolic scourges of our time.

描述(由申请人提供)：首席研究员罗伯特·萨尔吉斯博士致力于成为环境内分泌干扰、肥胖和新陈代谢领域的独立研究员。特别是萨尔吉斯博士将研究环境污染物对脂肪细胞代谢和胰岛素信号的影响，以了解这些化合物导致肥胖和糖尿病流行的分子机制。基于内分泌干扰物的研究表明，化学污染物可以改变内分泌信号，“环境肥胖假说”假定合成化学产品的指数增长与肥胖流行之间存在因果联系。这一应用的中心假设是，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对脂肪细胞代谢和胰岛素信号转导产生不利影响。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极大地促进我们对这些代谢紊乱的病理生理学的了解。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反应，刺激脂肪细胞分化，并诱导成熟脂肪细胞的胰岛素抵抗。为了研究环境内分泌干扰在脂肪细胞代谢和胰岛素信号转导中的作用，建议进行以下研究：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)确定糖皮质激素样内分泌干扰物不适当激活糖皮质激素受体从而诱导胰岛素抵抗的机制；以及3)表征内分泌干扰物诱导脂肪细胞基因表达的变化。总之，拟议的研究将极大地提高我们对环境内分泌干扰物在脂肪细胞代谢紊乱中的作用的理解，脂肪细胞代谢紊乱可能是肥胖和糖尿病祸害的部分基础。建议的项目将由Sargis博士在Matthew Brady博士和芝加哥大学内分泌学、糖尿病和新陈代谢部分的研究咨询委员会的指导下进行。这份申请是专门设计的，使萨尔吉斯博士能够在完成这一5年的奖励后过渡到作为助理教授的独立。已经制定了一项职业发展计划，通过获得生物化学和分子生物学的新研究技能以及精选的课程来帮助萨尔基斯博士实现这一目标。总的来说，这些经验将扩展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尖端研究。芝加哥大学为完成这一职业发展奖提供了一个丰富而充满活力的环境，布雷迪博士和许多其他熟练的调查人员都坚定地致力于帮助萨尔吉斯博士实现他成为一名独立科学家的目标。 与公共卫生相关：迅速增长的肥胖和糖尿病流行给我们的医疗保健系统带来了巨大的压力；然而，导致这些疾病的确切因素尚不完全清楚。拟议的研究将描述环境内分泌干扰化学物质通过干扰脂肪细胞代谢和胰岛素信号转导而促进肥胖和糖尿病发展的分子机制，特别是糖皮质激素信号转导的变化。了解环境污染物对肥胖和糖尿病发展的潜在贡献，将为制定合理的公共政策提供科学基础，以减轻环境掠夺对我们时代代谢祸害的影响。