Stimulated by Retinoic Acid (STra6) in Energy Homeostasis

视黄酸 (STra6) 刺激能量稳态

• 批准号: 7714745
• 负责人: Laura H Zemany
• 金额: $ 15.04万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7714745
• 关键词: Adenoviruses; Adipocytes; Adipose tissue; Affinity; All-Trans-Retinol; Antisense Oligonucleotides; Binding; Biochemistry; Body Composition; Cell Culture Techniques; Cells; Cellular biology; Cyclic AMP-Dependent Protein Kinases; Development; Development Plans; Diabetes Mellitus; Diet; Energy Metabolism; Esters; Fatty acid glycerol esters; Glucose; Glucose Intolerance; Glycogen; Goals; Grant; Homeostasis; Human; Injection of therapeutic agent; Insulin; Insulin Resistance; Knockout Mice; Laboratories; Lead; Liver; Measurement; Measures; Mediating; Mus; Muscle; Muscle Cells; Myogenin; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathway interactions; Phosphorylation Site; Plasmids; Production; Property; Recombinants; Research; Research Personnel; Research Project Grants; Retinoids; Retinol Binding Proteins; Rodent; Role; Serum; Signal Transduction; Skeletal Muscle; Techniques; Testing; Tissues; Training; Training Technics; Tretinoin; adipocyte differentiation; blood glucose regulation; career development; clinical application; design; glucose metabolism; glucose tolerance; glucose transport; glucose uptake; improved; in vivo; in vivo Model; insulin sensitivity; insulin signaling; insulin tolerance; new therapeutic target; overexpression; public health relevance; recombinase; research study; retinol binding protein receptor; skeletal; small hairpin RNA; uptake

DESCRIPTION (provided by applicant): This application is designed to facilitate the training and career development of the applicant, whose goal is to be an independent investigator. The proposed studies provide the applicant with a wide range of cell biology and biochemistry techniques to allow the applicant to develop expertise in diabetes research. The career development plan includes a compelling research project with potential clinical applications, laboratory technique training, and didactic scientific seminars. Type 2 diabetes is characterized by impaired insulin action in tissues such as muscle, liver, and adipose tissue. The long term objective is to determine the mechanisms involved in the pathogenesis of insulin resistance and diabetes. Retinol binding protein 4 (RBP4) is elevated in rodents and humans with obesity and insulin resistance. Injection of purified RBP4 in rodents causes insulin resistance, glucose intolerance, and impaired insulin signaling in skeletal muscle. STRA6 (Stimulated by retinoic acid) was recently identified as a high affinity receptor for RBP4. This grant will test the hypothesis that RBP4 causes insulin resistance in part through its interactions with STRA6 in tissues such as adipose tissue and skeletal muscle utilizing cell culture studies, primary tissue explants, and in vivo models. In specific aim #1, the importance of RBP4-STRA6 interactions in glucose metabolism and insulin signaling will be determined in cultured myocytes, and the applicant will investigate the mechanisms by which the RBP4-STRA6 pathway alters glucose homeostasis. Aim #2 will determine if STRA6 mediates RBP4-induced insulin resistance in skeletal muscle. This will be accomplished by determining glucose homeostasis in the skeletal muscle specific STRA6 knockout mouse and by measuring glucose uptake and insulin signaling in isolated muscle. Aim #3 will determine if RBP4-STRA6 interactions in adipose tissue alter whole body glucose homeostasis and the development of obesity. Glucose metabolism, insulin sensitivity, body composition, and energy expenditure will be studied in mice treated with STRA6 antisense oligonucleotides and in the adipose tissue STRA6 knockout mouse. Since STRA6 mediates the cellular uptake of retinol, serum and tissue levels of retinoids such as retinol and retinoic acid will be determined. PUBLIC HEALTH RELEVANCE: The proposed experiments will lead to a better understanding of mechanisms involved in the pathogenesis of insulin resistance and type 2 diabetes. New therapeutic targets to treat insulin resistance could be designed to target the retinoid-RBP4-STRA6 pathway.

描述（由申请人提供）： 该申请旨在促进申请人的培训和职业发展，其目标是成为一名独立的调查员。拟议的研究为申请人提供了广泛的细胞生物学和生物化学技术，使申请人能够发展糖尿病研究的专业知识。职业发展计划包括具有潜在临床应用的引人注目的研究项目，实验室技术培训和教学科学研讨会。2型糖尿病的特征在于组织如肌肉、肝脏和脂肪组织中胰岛素作用受损。长期目标是确定胰岛素抵抗和糖尿病发病机制。视黄醇结合蛋白4（RBP 4）在啮齿动物和肥胖和胰岛素抵抗的人类中升高。在啮齿动物中注射纯化的RBP 4会导致胰岛素抵抗、葡萄糖耐受不良和骨骼肌中胰岛素信号传导受损。STRA 6（由视黄酸刺激）最近被鉴定为RBP 4的高亲和力受体。这项资助将利用细胞培养研究、原代组织外植体和体内模型，检验RBP 4部分通过与脂肪组织和骨骼肌等组织中的STRA 6相互作用而导致胰岛素抵抗的假设。在具体目标#1中，将在培养的肌细胞中确定RBP 4-STRA 6相互作用在葡萄糖代谢和胰岛素信号传导中的重要性，并且申请人将研究RBP 4-STRA 6途径改变葡萄糖稳态的机制。目的#2将确定STRA 6是否介导骨骼肌中RBP 4诱导的胰岛素抵抗。这将通过测定骨骼肌特异性STRA 6敲除小鼠中的葡萄糖稳态和通过测量分离肌肉中的葡萄糖摄取和胰岛素信号传导来实现。目的#3将确定脂肪组织中的RBP 4-STRA 6相互作用是否改变全身葡萄糖稳态和肥胖的发展。将在用STRA 6反义寡核苷酸处理的小鼠和脂肪组织STRA 6敲除小鼠中研究葡萄糖代谢、胰岛素敏感性、身体组成和能量消耗。由于STRA 6介导视黄醇的细胞摄取，因此将测定类维生素A如视黄醇和视黄酸的血清和组织水平。 公共卫生关系：拟议的实验将导致更好地了解胰岛素抵抗和2型糖尿病的发病机制。治疗胰岛素抵抗的新的治疗靶点可以被设计为靶向类维生素A-RBP 4-STRA 6途径。