Environmental Endocrine Disruption of Adipocyte Metabolism

环境内分泌对脂肪细胞代谢的干扰

基本信息

批准号：
7953162
负责人：
Robert M Sargis
金额：
$ 15.68万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
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/7953162
关键词：
Acute Adipocytes Adipose tissue Advisory Committees Affect Animals Attention Award Binding 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 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 Resistance 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 research study response skills sound tool

项目摘要

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·萨吉斯（Robert Sargis）博士，努力成为环境内分泌干扰，肥胖和代谢领域界面的独立研究者。特别是Sargis博士将检查环境污染物对脂肪细胞代谢和胰岛素信号传导的影响，以了解这些化合物有助于肥胖和糖尿病流行病的分子机制。植根于内分泌破坏者研究，表明化学污染物可以改变内分泌信号传导，“环境肥胖基因假设”提出了合成化学生产的指数升高与肥胖症流行之间的因果关系。该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当调节将对脂肪细胞代谢和胰岛素信号传导产生不利影响。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显着提高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传导级联反应，刺激脂肪细胞分化，并在成熟的脂肪细胞中诱导胰岛素耐药性。为了研究环境内分泌破坏在脂肪细胞代谢和胰岛素信号传导中的作用，提出了以下研究：1）检查环境内分泌干扰物对成熟脂肪细胞中胰岛素信号传导的影响，以鉴定这些化学物质的分子靶标； 2）确定糖皮质激素样内分泌干扰物不适当地激活糖皮质激素受体的机制，从而诱导胰岛素耐药性； 3）表征内分泌干扰物诱导的脂肪细胞基因表达的改变。总而言之，拟议的研究将大大增强我们对环境内分泌破坏者在脂肪细胞代谢扰动中的作用的理解，这可能部分是肥胖和糖尿病祸害的基础。拟议的项目将由萨吉斯博士在Matthew Brady博士的指导下，以及芝加哥大学内分泌，糖尿病和代谢部分的研究咨询委员会的指导。该申请是专门设计的，目的是使Sargis博士在完成这项5年奖励后的助理教授过渡为独立。已经制定了一项职业发展计划，以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吉斯博士实现这一目标。总的来说，这些经验将扩大萨吉斯博士的知识库，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。芝加哥大学提供了一个丰富而充满活力的环境，以完成这一职业发展奖，布雷迪博士以及许多其他熟练的研究人员都致力于帮助萨吉斯博士实现成为独立科学家的目标。公共卫生相关性：新兴的肥胖症和糖尿病流行病正在为我们的医疗保健系统带来巨大的菌株；但是，造成这些疾病的确切因素是不完全理解的。拟议的研究将表征分子机制，通过这种机制，环境内分泌化学物质通过破坏脂肪细胞代谢和胰岛素信号的破坏，促进糖皮质激素信号的改变，从而有助于肥胖和糖尿病的发展。了解环境污染物对肥胖和糖尿病的发展的潜在贡献将为制定旨在减轻环境倾向对我们这个时代代谢性祸害的影响的合理公共政策提供科学基础。