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

NR4A Orphan Receptors And Insulin Resistance

NR4A 孤儿受体和胰岛素抵抗

基本信息

批准号：
8116981
负责人：
W Timothy GARVEY
金额：
$ 46.68万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8116981
关键词：
2,4-thiazolidinedione 9-deoxy-delta-9-prostaglandin D2 Address Adipocytes Adipose tissue Adverse effects Affect Agonist Animals Biopsy Blood Glucose Blood Plasma Volume Body Composition Body Weight Body Weight decreased Cell Culture System Cell Differentiation process Cell Line Cells Cellular Stress Clinical Cultured Cells Data Development Diabetes Mellitus Diabetes prevention Diet Disease Drug Delivery Systems Drug effect disorder Exhibits Family Family member Fatty acid glycerol esters GLUT4 gene Gene Expression Genes Goals Health Heart Heart failure Human Individual Infusion procedures Insulin Insulin Resistance Investigation Isoprostanes Laboratories Ligands Lipids Liver Measures Mediating Mediator of activation protein Metabolic Metabolic Diseases Metabolic syndrome Metabolism Molecular Monitor Mus Muscle Muscle Cells NR4A1 gene Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Orphan Receptor Obesity Orphan Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphorylation Prediabetes syndrome Prevention Process Proteins Research Resistance Rodent Rodent Model Role Signal Transduction Signaling Molecule Skeletal Muscle Small Interfering RNA Subgroup Testing Therapeutic Therapeutic Intervention Thiazolidinediones Time Tissue-Specific Gene Expression Tissues Trans-Activators Transgenic Mice Translational Research Weight Gain Work adipocyte-specific fatty acid-binding protein adipokines base biological adaptation to stress cDNA Arrays cardiovascular disorder risk cyclopentenone diabetes control effective therapy feeding glucose tolerance glucose transport glucose uptake in vivo insulin sensitivity insulin signaling lifestyle intervention lipid mediator lipid metabolism macrophage metabolic abnormality assessment novel osmotic minipump prevent promoter prostaglandin A2 receptor small hairpin RNA subcutaneous therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): Insulin resistance is central to the pathogenesis of Type 2 Diabetes (T2DM) and the Metabolic Syndrome, and drugs or lifestyle interventions that increase insulin sensitivity constitute effective therapy and prevention. Thiazolidinedione drugs (TZDs) act through agonism of nuclear transcription factors (i.e., PPAR3) to enhance insulin sensitivity; however, TZD therapy is associated with adverse effects, including weight gain and heart failure. These untoward effects limit clinical utility, and highlight the need for alternative insulin-sensitizing medications that can act directly on muscle. We will study the NR4A family of orphan nuclear receptors, which were identified as differentially expressed genes on our human muscle cDNA microarrays. Extensive preliminary data indicate that: (i) NR4A3 is expressed at lower levels in insulin-resistant humans and rodents; (ii) TZDs induce NR4A3 suggesting that NR4A3 may be downstream of TZD action; (iii) MCK-NR4A3 transgenic mice exhibit an insulin sensitive phenotype; (iv) an increase in NR4A3 receptors can augment insulin signaling and stimulation of glucose transport; (v) PGA2 acts to increase insulin sensitivity in a NR4A3 dependent manner. To pursue these novel observations, our overall goal is to increase our understanding of the role of NR4A receptors in modulating insulin action, their role in human insulin resistance, and their rationale as a therapeutic drug target. To achieve this goal, we will apply our laboratory's capacity for translational research including human metabolism, human muscle and adipose tissue biopsies, transgenic mice, and cultured cell systems. Based on extensive preliminary data, the specific aims are: (1) Assess expression of NR4A receptors in muscle and fat in insulin sensitive, insulin resistant, and T2DM humans, before and after weight loss and TZD treatment, and in insulin resistant rodent models. (2) Establish metabolic role of NR4A3 by phenotyping transgenic mice with specific hyperexpression of NR4A3 in skeletal muscle. In both human and mouse, NR4A expression will be assessed for its ability to affect insulin sensitivity and substrate metabolism at the level of whole body and individual cells and tissues. (3) Determine mechanisms by which NR4A3 regulates insulin action by studying stable hyperexpression and shRNA- mediated suppression of NR4A3 in cultured muscle and adipose cells. These studies will address our preliminary data indicating that NR4A3 modulates insulin-stimulated glucose transport, GLUT4 translocation, and insulin-mediated phosphorylation of signaling molecules. (4) Identify lipid mediator agonists of NR4A3 based on preliminary data indicating that PGA2 increases insulin sensitivity in a NR4A3 dependent manner. Thus, this work will elucidate novel molecules and pathophysiologic processes contributing to insulin resistance, and develop new potential drug targets for the treatment and prevention of diabetes and cardiometabolic disease. PUBLIC HEALTH RELEVANCE: Insulin resistance is a critical factor causing Type 2 Diabetes and the Metabolic Syndrome. Treatment of insulin resistance can prevent diabetes and control blood sugars in patients who already have the disease; however, the available medications have serious side effects which limit their use. This research will elucidate, for the first time, the role of a novel family of orphan nuclear transcription factors (NR4A) in the cause of insulin resistance, and their potential as targets for new drugs to treat and prevent Type 2 Diabetes.

描述（由申请人提供）：胰岛素抵抗是2型糖尿病（T2DM）和代谢综合征发病机制的核心，增加胰岛素敏感性的药物或生活方式干预是有效的治疗和预防。噻唑烷二酮类药物（TZDs）通过核转录因子（即PPAR3）的激动作用增强胰岛素敏感性；然而，TZD治疗有副作用，包括体重增加和心力衰竭。这些不良影响限制了临床应用，并强调需要替代胰岛素增敏药物，可以直接作用于肌肉。我们将研究孤儿核受体NR4A家族，该家族在我们的人类肌肉cDNA微阵列上被鉴定为差异表达基因。大量初步数据表明：(i) NR4A3在胰岛素抵抗的人和啮齿动物中表达水平较低；（ii） TZD诱导NR4A3，提示NR4A3可能在TZD作用的下游；（iii） MCK-NR4A3转基因小鼠表现出胰岛素敏感表型；（iv） NR4A3受体的增加可以增强胰岛素信号传导和刺激葡萄糖转运；(v) PGA2以NR4A3依赖的方式增加胰岛素敏感性。为了追求这些新的观察结果，我们的总体目标是增加我们对NR4A受体在调节胰岛素作用中的作用的理解，它们在人类胰岛素抵抗中的作用，以及它们作为治疗药物靶点的原理。为了实现这一目标，我们将运用我们实验室的能力进行转化研究，包括人体代谢、人体肌肉和脂肪组织活检、转基因小鼠和培养细胞系统。基于广泛的初步数据，具体目的是：(1)评估胰岛素敏感、胰岛素抵抗和T2DM人、减肥和TZD治疗前后以及胰岛素抵抗啮鼠模型中肌肉和脂肪中NR4A受体的表达。(2)通过对NR4A3在骨骼肌中特异性高表达的转基因小鼠进行表型分析，建立NR4A3的代谢作用。在人类和小鼠中，将评估NR4A表达在整个身体和单个细胞组织水平上影响胰岛素敏感性和底物代谢的能力。(3)通过研究NR4A3在培养的肌肉和脂肪细胞中的稳定高表达和shRNA介导的抑制，确定NR4A3调控胰岛素作用的机制。这些研究将解决我们的初步数据，表明NR4A3调节胰岛素刺激的葡萄糖转运、GLUT4易位和胰岛素介导的信号分子磷酸化。(4)根据初步数据确定NR4A3脂质介质激动剂，表明PGA2以NR4A3依赖的方式增加胰岛素敏感性。因此，这项工作将阐明胰岛素抵抗的新分子和病理生理过程，并为治疗和预防糖尿病和心脏代谢疾病开发新的潜在药物靶点。公共卫生相关性：胰岛素抵抗是导致2型糖尿病和代谢综合征的关键因素。治疗胰岛素抵抗可以预防糖尿病并控制已经患有糖尿病的患者的血糖；然而，现有的药物有严重的副作用，限制了它们的使用。这项研究将首次阐明一个新的孤儿核转录因子家族（NR4A）在胰岛素抵抗中的作用，以及它们作为治疗和预防2型糖尿病新药的潜在靶点。