权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Environmental Programming of Insulin Resistance

胰岛素抵抗的环境规划

基本信息

批准号：
9174318
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 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9174318
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 Cd68 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 Epidemiologic Studies 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 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 Oxygen Consumption Pathway interactions Phenotype Pregnancy Pregnant Women Prevention strategy Primary Cell Cultures Receptor Signaling Research Research Personnel Risk Risk Factors Sheep Signal Pathway Signal Transduction Signaling Molecule Skeletal Muscle 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 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