Functional aspects of SREBP1c in intact skeletal muscle

SREBP1c 在完整骨骼肌中的功能方面

• 批准号: 7010383
• 负责人: Paul S. Maclean
• 金额: $ 13.23万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7010383
• 关键词: Adenoviridae; binding proteins; biological signal transduction; gene delivery system; gene expression; genetic regulation; genetically modified animals; insulin sensitivity /resistance; laboratory mouse; lipid metabolism; microarray technology; muscle metabolism; polymerase chain reaction; protein structure function; striated muscles; transfection /expression vector

DESCRIPTION (provided by applicant): Dr. MacLean has trained in the areas of muscle physiology, lipid metabolism, and the regulation of gene expression in skeletal muscle. This proposal includes didactic training, research skill development, and a mentored research project, that will foster his development into an independent academic scientist. The research plan is focused on studying the regulation of skeletal muscle lipid metabolism in an in vivo model of adenoviral gene delivery. In the liver, mammary, and adipose tissue, there is evidence to suggest that sterol response element binding proteins (SREBPs), a family of transcription factors, mediate the nutritional regulation of the expression of genes involved in cholesterol, triglycerides, and carbohydrate metabolism. One particular isoform, SREBP1c, has been implicated in regulating gene expression in such a manner as to promote an enzymatic profile that would promote the accumulation of lipids. Because of this link to lipid accumulation, it has been hypothesized that the dysregulation of SREBP1c may be contributing to the lipid abnormalities commonly found with tissues in the metabolic syndrome. SREBP1c is also expressed in skeletal muscle, but its regulation and function in this tissue have not been elucidated. The work in the mentored research project will further characterize a novel in vivo approach to study gene function in skeletal muscle and employ it to examine the gene targets and physiological effects of SREBP1c in this tissue. First, a model of adenoviral gene delivery to skeletal muscle will be characterized with respect to the immediacy and duration of transduction, the titer requirements for transduction efficacy, and the time course of the accompanying immune response. Second, adenoviral vectors containing expression cassettes for the dominant positive or dominant inhibitory forms of SREBP1c will be used with the model to identify the genes that are sensitive to SREBP1c regulation. Third, the same adenoviral vectors will be used with the model to examine the effects of SREBP1c on muscle lipid metabolism. Having a better understanding of the function and interaction of genes expressed in skeletal muscle may lead to novel therapeutic strategies of muscle-related diseases. This award will provide: 1) the means to apply new techniques to his research program; 2) a formal plan for interaction with well-established, successful investigators; and 3) an opportunity for him to mature his research, teaching, and administrative skills, in an excellent research environment.

描述（由申请人提供）：麦克林博士在肌肉生理学，脂质代谢和骨骼肌中基因表达的调节方面接受过培训。该建议包括教学培训，研究技能发展和一个指导的研究项目，这将使他的发展成为独立的学术科学家。该研究计划的重点是研究在腺病毒基因递送体内模型中骨骼肌脂质代谢的调节。在肝脏，乳腺和脂肪组织中，有证据表明，固醇反应元件结合蛋白（SREBPS）（一种转录因子家族）介导了涉及胆固醇，甘油三酸酯和碳水化合物的基因表达的营养调节。一种特殊的同工型SREBP1C已与促进酶促谱的方式调节基因表达，以促进脂质的积累。由于这种与脂质积累的联系，已经假设SREBP1C的失调可能导致代谢综合征中组织中常见的脂质异常。 SREBP1C在骨骼肌中也表达，但尚未阐明其在该组织中的调节和功能。指导研究项目中的工作将进一步描述一种新型的体内方法来研究骨骼肌中基因功能，并采用它来检查SREBP1C在该组织中的基因靶标和生理效应。首先，将腺病毒基因递送到骨骼肌的模型将以转导的直接性和持续时间，转导功效的滴度要求以及随附的免疫反应的时间过程来表征。其次，将与模型一起使用含有主导阳性或显性抑制形式的表达盒的腺病毒载体，以识别对SREBP1C调节敏感的基因。第三，将与模型一起使用相同的腺病毒载体来检查SREBP1C对肌肉脂质代谢的影响。更好地了解在骨骼肌中表达的基因的功能和相互作用可能会导致与肌肉相关疾病的新型治疗策略。该奖项将提供：1）将新技术应用于其研究计划的手段； 2）与建立良好，成功的调查人员互动的正式计划； 3）在出色的研究环境中，他有机会使他的研究，教学和行政技能成熟。