Environmental Programming of Insulin Resistance

摘要 这个K22职业发展奖的目标是促进Veiga-Lopez博士的独立之路， 一位环境内分泌学家，并为她的长期目标提供手段；成为 环境发展规划领域。这项提议的短期目标是收购 以下方面的必要培训、指导和技能：1)氧化应激/线粒体功能 方法，2)炎症途径，3)最新的基因组学和系统生物学方法。为 为此，已与诺伯特·卡明斯基博士共同制定了详细的职业发展计划(CDP)， 目前的提案和免疫毒理学专家，以及一个由多学科调查人员组成的团队 咨询委员会成员。CDP包括课程作业、研讨会、研讨会和会议， 以及与赞助者和咨询委员会的会议，这与研究计划一起将使 在K22的3年内成功生成竞争对手R01应用程序的初步数据的候选人 获奖。就此而言，作为密歇根州立大学的新助理教授，候选人拥有 必要的设施，以制定以环境研究为重点的强有力的研究计划。2012年， 美国糖尿病协会估计，有2230万美国人被诊断为糖尿病。胰岛素 抵抗是2型糖尿病病理生理学的早期征象之一。类型2中令人震惊的数字 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 人类暴露于内分泌干扰物双酚A(BPA)与胰岛素抵抗之间的关系。 动物研究进一步支持了这一证据。然而，BPA可能导致这种情况的机制 中断情况仍不得而知。这一建议的中心假设是，产前接触双酚A会导致 导致氧化应激、促炎状态和细胞内增加的microRNA的变化 能量通路功能障碍导致胰岛素抵抗的发病，这是2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 了解基本共享机制…例如，炎症、表观遗传变化、氧化应激、 诱变等，是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“。这项提案将通过以下方式审查基本机制 哪种双酚A可通过胎儿期miRNAs的变化诱导组织特异性氧化应激和炎症 生命，使用一个大型动物模型。体外方法也将被用于研究双酚A是否会导致干扰 在细胞内的能量通路中，触发氧化应激的开始，并促进 胰岛素抵抗。了解无处不在的内分泌干扰物 作为BPA的诱因，这些中断将使预防策略能够在最脆弱的时期之一 暴露在环境中--胎儿早期发育。

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.