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Environmental Programming of Insulin Resistance

胰岛素抵抗的环境规划

基本信息

批准号：
9538708
负责人：
Almudena Veiga-Lopez
金额：
$ 15.47万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9538708
关键词：
3-nitrotyrosine Adipocytes Adipose tissue Adult Adult Children Advisory Committees Affect American Animal Model Animals Antioxidants Area Bioinformatics Biological Assay Cardiovascular Diseases Cell Line Comorbidity Complex Coupling Cytokine Activation DNA Damage Data Defect Development Development Plans Diabetes Mellitus Diagnosis Diet Disease Dose Down-Regulation Educational workshop Embryo Endocrine Disruptors Endocrinologist Environment Environmental Exposure Epigenetic Process Exposure to Fatty acid glycerol esters Fetal Development Fetal Liver Fetal Viability Fetus First Pregnancy Trimester Functional disorder Gene Expression Genome Genomics Gestational Diabetes Glutathione Goals Health Hepatocyte Homeostasis Human Hyperinsulinism Hypertension Immune Impairment In Vitro Inflammation Inflammatory Inflammatory Response Insulin Insulin Receptor Insulin Resistance Intervention K-Series Research Career Programs K22 Award Lead Life Liver Low Birth Weight Infant Measurement Measures Mentors Messenger RNA Metabolic Methods Michigan MicroRNAs Mitochondria Modeling Molecular Muscle Muscle Cells Mutagenesis National Institute of Environmental Health Sciences Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Stress Oxidative Stress Pathway Oxides Oxygen Consumption Pathway interactions Phenotype Pregnancy Pregnant Women Prevention strategy Preventive Intervention Primary Cell Cultures Quantitative Reverse Transcriptase PCR Research Research Personnel Risk Risk Factors Sheep Signal Pathway Signal Transduction Signaling Molecule Skeletal Muscle Small RNA Strategic Planning Stress System Systems Biology Testing Tissues Toxic Environmental Substances Toxicity Tests Toxicology Training Transcript Universities Western Blotting Woman Work biological adaptation to stress bisphenol A career career development endocrine disruptor exposure environmental change epidemiology study estrogenic activity fetal fetus cell in vivo insulin sensitivity meetings member multidisciplinary nitrosative stress novel offspring postnatal pregnant prenatal prenatal exposure professor programs protein expression response skills symposium transcription factor transcriptome sequencing translational study xenoestrogen

项目摘要

ABSTRACT The goal of this K22 Career Development Award is to facilitate the path to independence to Dr. Veiga-Lopez, an environmental endocrinologist, and provide with the means towards her long-term goal; become a leader in the field of environmental developmental programming. The short-term goals of this proposal are to acquire the necessary training, mentoring, and skills in the following areas: 1) oxidative stress / mitochondrial function methods, 2) inflammatory pathways, and 3) state of the art genomics and systems biology approaches. For that, a detailed Career Development Plan (CDP) has been developed with Dr. Norbert Kaminski, Sponsor of the current proposal and expert in immune-toxicology, and a multidisciplinary team of investigators that are members of the Advisory Committee. The CDP includes course work, workshops, seminars, and conferences, and meetings with the Sponsor and Advisory Committee, which along with the Research Plan will enable the candidate to successfully generate preliminary data for a competitive R01 application within 3 years of the K22 award. To that effect, as a new Assistant Professor at Michigan State University, the candidate has the necessary facilities to develop a strong research program focusing on environmental research. In 2012, the American Diabetes Association estimated that 22.3 million Americans were diagnosed with diabetes. Insulin resistance is one of the early signs in the pathophysiology of type 2 diabetes. Staggering numbers in type 2 diabetes cases over the past decades may relate to environmental exposures. Recent evidence suggests an association between exposure to the endocrine disruptor bisphenol A (BPA) and insulin resistance in humans. Animal studies further supports this evidence. However, the mechanisms by which BPA may induce such disruptions remain unknown. The central hypothesis of this proposal is that prenatal exposure to BPA leads to changes in microRNAs responsible for increased oxidative stress, pro-inflammatory state, and intracellular energy pathways dysfunction leading to the onset of insulin resistance, the first step in the development of type 2 diabetes. This hypothesis aligns with the first goal in the 2012-2017 NIEHS Strategic Plan: “Identify and understand fundamental shared mechanisms…, e.g., inflammation, epigenetic changes, oxidative stress, mutagenesis, etc., underlying a broad range of complex diseases, in order to enable the development of applicable prevention and intervention strategies”. This proposal will examine the underlying mechanisms by which BPA can induce tissue specific oxidative stress and inflammation via changes in miRNAs during prenatal life, using a large animal model. In vitro approaches will also be used to investigate if BPA leads to disruption in intracellular energy pathways triggering the onset of oxidative stress and contributing to the development of insulin resistance. Understanding the underlying mechanisms by which a ubiquitous endocrine disruptor such as BPA, induces these disruptions will enable prevention strategies during one of the most vulnerable periods of exposure - early fetal development.

摘要这个K22职业发展奖的目标是促进Veiga-Lopez博士独立的道路，一个环境内分泌学家，并提供实现她的长期目标的手段;成为领导者，环境发展规划领域。该提案的短期目标是获得在以下领域进行必要的培训，指导和技能：1）氧化应激/线粒体功能方法，2）炎症途径，和3）现有技术的基因组学和系统生物学方法。为一个详细的职业发展计划（CDP）已经与诺伯特·卡明斯基博士，赞助商，目前的建议和免疫毒理学专家，以及一个多学科的研究小组，咨询委员会成员。CDP包括课程工作，讲习班，研讨会和会议，以及与申办者和咨询委员会的会议，这些会议沿着研究计划将使候选人在K22的3年内成功生成竞争性R 01应用的初步数据奖为此，作为密歇根州立大学的新助理教授，候选人有必要的设施，以发展强大的研究计划，重点是环境研究。2012年美国糖尿病协会估计，2230万美国人被诊断患有糖尿病。胰岛素抵抗是2型糖尿病病理生理学的早期征兆之一。类型2中的惊人数字过去几十年的糖尿病病例可能与环境暴露有关。最近的证据表明，暴露于内分泌干扰物双酚A（BPA）和人类胰岛素抵抗之间的联系。动物实验进一步证实了这一点。然而，BPA可能引起这种反应的机制中断情况仍然未知。这项建议的核心假设是，产前暴露于BPA会导致负责增加氧化应激、促炎状态和细胞内能量通路功能障碍导致胰岛素抵抗的发生，这是型糖尿病发展的第一步。 2糖尿病.这一假设与2012-2017年NIEHS战略计划的第一个目标一致：“确定和了解基本的共享机制，例如，炎症，表观遗传变化，氧化应激，诱变等，一系列复杂疾病的基础，以便能够发展适用的预防和干预战略”。本提案将通过以下方式审查基本机制： BPA可以通过产前期间miRNAs的变化诱导组织特异性氧化应激和炎症，生活，使用大型动物模型。体外方法也将用于研究BPA是否会导致破坏在细胞内能量途径引发氧化应激的发生，并有助于发展胰岛素抵抗了解一种普遍存在的内分泌干扰物，如双酚A，诱导这些中断将使预防战略在一个最脆弱的时期，早期胎儿发育。