Environmental Circadian Disruptors Increase Diabetes and Metabolic Disorders Risk

环境昼夜节律干扰物会增加糖尿病和代谢紊乱的风险

基本信息

批准号：
8875686
负责人：
Margarita L Dubocovich
金额：
$ 19.88万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8875686
关键词：
Accounting Adult Affect Affinity Algorithms Animal Model Attenuated Beta Cell Binding Biological Clocks Blindness Carbaryl Cell Proliferation Cells Chemicals Chinese Hamster Ovary Cell Circadian Rhythms Computer Simulation Consensus Cyclic AMP Data Diabetes Mellitus Diagnosis Endocrine Disruptors Endocrine system Equilibrium Exploratory/Developmental Grant for Diagnostic Cancer Imaging Exposure to Fingerprint Forskolin Foundations Future Gene Expression Generations Glucose Goals Guanosine Triphosphate Guidelines Health Heart Diseases Hormones Human Hypothalamic structure In Vitro Incidence Insecticides Insulin Islets of Langerhans Kidney Failure Knockout Mice Lead Ligands Lipid Peroxidation Lower Extremity Luciferases Mammalian Cell Measures Mediating Melatonin Melatonin Receptors Metabolic Diseases Metabolic syndrome Modeling Nervous System Physiology Non-Insulin-Dependent Diabetes Mellitus Obesity Pancreas Peripheral Physiological Physiological Processes Physiology Pineal gland Protein Kinase C Rattus Receptor Signaling Receptor, Melatonin, MT1 Receptor, Melatonin, MT2 Reporter Genes Reproduction Rest Risk Risk Factors Signal Transduction Stroke Structure of beta Cell of islet System Testing Time Tissues Toxic Environmental Substances Withdrawal Work base desensitization design diabetes risk disorder risk environmental agent environmental chemical glucose metabolism high throughput screening immune function in vitro Bioassay insulin secretion knowledge base limb amputation man pharmacophore receptor receptor binding receptor function receptor sensitivity research study screening suprachiasmatic nucleus three-dimensional modeling toxicant virtual

项目摘要

DESCRIPTION (provided by applicant): Exposure to environmental chemicals is a major concern for human health as natural and man-made substances can adversely affect physiological processes which may contribute to the incidence of obesity, metabolic syndrome, and type 2 diabetes. In adults, type 2 diabetes accounts for about 90% of diagnosed diabetes cases and is a major risk factor for heart disease, stroke, kidney failure, non-traumatic lower-limb amputations and blindness. The goal of this proposal is to identify endocrine disruptors affecting the circadian hormone melatonin and its ability to signal "time-of-day" messages to target peripheral tissues. The release of melatonin from the pineal gland is regulated by biological clocks in the suprachiasmatic nucleus (SCN) of the hypothalamus which in turn regulates peripheral target tissues through activation of MT1 and MT2 melatonin receptors. In pancreatic ß-cells, disruption of melatonin receptor signaling may alter homeostatic rhythmic balance of glucose metabolism and insulin release leading to diabetes and metabolic disorders. Our overarching hypothesis is that, certain classes of environmental chemicals act as circadian disruptors by persistent and irregular activation and/or blockade of melatonin receptors in the SCN and in target peripheral tissues (eg. pancreatic islets). Specific aims designed to accomplish our goals are: 1) to use an integrated pharmacoinformatics approach to identify environmental circadian disruptors from a knowledgebase of environmental agents using in silico 2D/3D melatonergic pharmacophore fingerprinting; 2a) to iteratively assess ligand affinity, selectivity and efficacy of environmental disruptors in competition for 2[125I]- iodomelatonin binding to hMT1 and hMT2 melatonin receptors expressed in mammalian CHO cells both in the absence and presence of GTP, and 2b) to modulate forskolin-mediated CRE-luciferase reporter gene expression and insulin secretion via functional activation of rat melatonin receptors expressed in rat INS1 ß-cells; 3) To determine the potential of selected environmental chemicals to alter the rhythmic homeostatic balance of diabetes markers through changes of melatonin receptor sensitivity and signaling in rat INS-1 pancreatic ß-cells (MT1) altering MT1-mediated sensitization and in SCN 2.2 cells by attenuating melatoin- mediated inhibition of cAMP formation (MT1, MT2) and Protein Kinase C stimulation (MT2) using in vitro bioassays. Furthermore, cell proliferation, and lipid peroxidation in pancreatic b-cells will be measured to assess the potential of these disruptors to increase the risk of diabetes associated metabolic disorders. Our integrated Chem2Risk strategy will provide the essential impetus to pursue further testing in animal models and be useful in future assessment of risk factors associated with environmental disruptors carrying similar chemical-structural features and to establish exposure regulatory guidelines.

描述（由适用提供）：对环境化学物质的接触是人类健康的主要问题，因为天然和人造物质可能会对物理过程产生不利影响，这可能导致肥胖，代谢综合征和2型糖尿病的事件。在成人中，2型糖尿病约占诊断性糖尿病病例的90％，是心脏病，中风，肾衰竭，非创伤性下limb截肢和失明的主要危险因素。该提案的目的是确定影响昼夜节律激素褪黑激素的内分泌干扰物及其向靶向外围组织的“时间”消息发出信号的能力。下丘脑的核核（SCN）中，从松果体中释放褪黑激素的释放受到调节，这又通过激活MT1和MT2褪黑激素受体来调节外周靶组织。胰腺β细胞，褪黑激素受体信号传导的破坏可能会改变葡萄糖代谢和胰岛素释放的稳态节奏平衡，从而导致糖尿病和代谢性疾病。我们的总体假设是，某些类型的环境化学品通过SCN和靶向外围组织中的褪黑激素受体的持续和不规则激活和/或阻断（例如胰腺胰岛）来起到昼夜节律破坏者的作用。旨在实现我们的目标的具体目的是：1）使用综合药物信息信息方法来识别使用硅2D/3D褪黑激素药物团指纹的环境剂中的环境昼夜节律破坏者； 2a) to iteratively assess ligand affinity, selectivity and efficiency of environmental disruptors in competition for 2[125I]- iodomelatonin binding to hMT1 and hMT2 melatonin receptors expressed in mammalian CHO cells both in the absence and presence of GTP, and 2b) to modulate forskolin-mediated CRE-luciferase reporter gene expression and insulin secretion via functional在大鼠ins1ß细胞中表达的大鼠褪黑激素受体的激活； 3）确定所选环境化学物质的潜力，以改变褪黑激素受体受体的灵敏度和信号传导的变化，以改变糖尿病受体的节律体内平衡，并通过在scn 2.2细胞中改变MT1介导的MT1介导的MT1-介导的MTERIDINAT-METINTIC（MT1）的MT1介导的MTISERATION（MT1）的MT1介导的MT1介导（MT1）的信号传导（MT1）。激酶C刺激（MT2）使用体外生物测定。此外，将测量胰腺B细胞中的细胞增殖和脂质过氧化，以评估这些破坏者增加糖尿病相关代谢性疾病的风险的潜力。我们的集成Chem2Risk策略将为动物模型中的进一步测试提供基本动力，并在对与具有相似化学结构特征的环境破坏者相关的危险因素评估中有用，并确定暴露于暴露的调节指南。