Environmental Programming of Insulin Resistance

胰岛素抵抗的环境规划

• 批准号: 9341307
• 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
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9341307
• 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

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.

抽象的 这个K22职业发展奖的目标是促进通往Veiga-Lopez博士的独立之路， 环境内分泌学家，并为她的长期目标提供手段；成为领导者 环境发展编程领域。该提议的短期目标是获取 以下领域的必要培训，心理和技能：1）氧化应力 /线粒体功能 方法，2）炎症途径和3）艺术基因组学和系统生物学方法的状态。为了 这是一项详细的职业发展计划（CDP） 当前的建议和免疫毒理学专家，以及一个多学科研究人员团队 咨询委员会成员。 CDP包括课程工作，讲习班，半小伙和会议， 以及与赞助商和咨询委员会的会议，该委员会将与研究计划一起 候选人在K22的3年内成功生成竞争性R01应用程序的初步数据 奖。为此，作为密歇根州立大学的新助理教授，候选人拥有 开发针对环境研究的强大研究计划的必要设施。 2012年 美国糖尿病协会估计，有2230万美国人被诊断出患有糖尿病。胰岛素 抗性是2型糖尿病病理生理学的早期迹象之一。类型2中的惊人数字 在过去的几十年中，糖尿病病例可能与环境暴露有关。最近的证据表明 在人类中暴露于内分泌破坏者双酚A（BPA）和胰岛素抵抗之间的关联。 动物研究进一步支持这一证据。但是，BPA可能影响此类机制 中断仍然未知。该提议的中心假设是，产前暴露于BPA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发作，这是类型发展的第一步 2个糖尿病。该假设与2012-2017 NIEHS战略计划中的第一个目标保持一致：“识别和 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，存在广泛的复杂疾病，以便能够发展 适用的预防和干预策略”。该提案将检查 哪种BPA可以在产前期间通过miRNA的变化诱导组织特异性氧化应激和注射 生活，使用大型动物模型。体外方法也将用于研究BPA是否导致破坏 在细胞内能通路中，触发氧化应激的发作，并有助于发展 胰岛素抵抗。了解无处不在的内分泌破坏者这样的基本机制 作为BPA，诱导这些中断将在最脆弱的时期之一实现预防策略 暴露 - 早期胎儿发育。