Role of GH on thiol metabolism, stress resistance and aging

GH 对硫醇代谢、应激抵抗和衰老的作用

• 批准号: 8323370
• 负责人: HOLLY M. BROWN-BORG
• 金额: $ 11.49万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323370
• 关键词: Activities of Daily Living; Address; Affect; Aging; Aging-Related Process; Animals; Area; Award; Bioinformatics; Biomedical Research; Cellular Stress; Centers of Research Excellence; DNA Methylation; Development; Diet; Disease; Environment; Epigenetic Process; Exercise; Faculty; Family member; Future; Genes; Glutathione; Glutathione Disulfide; Glutathione Metabolism Pathway; Glutathione S-Transferase; Grant; Growth Hormone Receptor; Health; Health Sciences; Human; IGF1 gene; Knock-out; Knockout Mice; Laboratory Animal Production and Facilities; Life; Link; Longevity; Mass Spectrum Analysis; Metabolic; Metabolic Pathway; Metabolism; Methionine; Mitochondria; Modeling; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Nature; North Dakota; Organism; Pathway interactions; Pattern; Play; Postdoctoral Fellow; Predisposition; Process; Protein S; Proteins; Proteomics; Regulation; Research; Research Training; Resistance; Resources; Role; Science; Scientist; Signal Pathway; Signal Transduction; Somatomedins; Somatotropin; Stress; Sulfhydryl Compounds; System; Testing; Therapeutic Intervention; Thioredoxin; Time; Tissues; Training; Transgenic Organisms; United States National Institutes of Health; Universities; Up-Regulation; Wild Type Mouse; Work; age related; design; epigenomics; glutaredoxin; graduate student; growth hormone deficiency; innovation; medical schools; mutant mouse model; programs; protein expression; research study; respiratory; stressor; tool

PROJECT SUMMARY The short term objectives of this KO2 proposal are: 1) to increase the time devoted to conduct and complete experiments of a recently awarded RO1; and 2) to complete exercises designed to enhance and enrich the applicants focus and expertise in the areas of aging and epigenetics. The long-term objective of the KO2 is to effectively utilize both 1) and 2) to enhance the training of graduate students, post docs, faculty (not currently practicing in the field of aging) and undergraduates, in particular, in aging research and to obtain additional support in future years. The research environment at the University of North Dakota School of Medicine & Health Sciences is active and growing. Two major NIH grants (INBRE, COBRE) over the last 8 years have increased the resources available to the basic scientists. The Proteomics/Mass Spectrometry core, a core in Bioinformatics that is under development and the Center for Biomedical Research (animal facilities) will be utilized by the applicant. The applicant has developed an active research program at UND with the current tools available and plans to increase those activities during the period of the award and beyond. The objective of the science integral to this proposal is to delineate mechanisms of the beneficial effects of growth hormone deficiency on mitochondrial function, stress resistance and health span. Our research has been focused on understanding the hypothesis that in long living animals, an upregulation of thiol metabolism leads to greater protection from cellular stress. The applicant's work has established that reduced growth hormone (GH) signaling is a major player in longevity assurance. The global hypothesis to be tested is that thiol metabolism plays a key role in aging and that GH modulates key components of this pathway ultimately leading to changes in health span (via stress resistance/protection) and lifespan. Thus, reduced GH signaling confers a biologic advantage to dwarf mice leading to better scavenging of toxic metabolic byproducts, altered mitochondrial function and enhanced longevity. To further address and define this global hypothesis the applicant plans to elucidate the relationship between GH, thiol metabolism and cellular protection by: 1) directly linking the enhanced respiratory and antioxidative activities in dwarf mice to increased mitochondrial GSH and glutathionylation of these proteins; 2) providing direct evidence that the lack of GH is responsible for substrate-specific enhancement of the GST system; 3) defining the changes in thiol metabolism linked to stress resistance and longevity following altered dietary MET; and 4) establishing the first epigenomic profile of a long-living mouse. Determining GH-dependent pathways and mechanisms may suggest therapeutic interventions to enhance stress resistance, delay aging, treat aging-related disorders and extend health span in humans.

项目摘要 该KO2提案的短期目标是：1）增加专门进行进行的时间和 最近授予的RO1的完整实验； 2）完成旨在增强和的练习 丰富申请人在衰老和表观遗传学领域的重点和专业知识。长期目标的 KO2将有效利用1）和2）来增强研究生的培训，邮政文档， 教师（目前不在衰老领域实践），特别是在衰老研究中的本科生 并在未来几年获得额外的支持。北大学的研究环境 达科他州医学与健康科学学院活跃和成长。两个主要的NIH赠款（Inbre， 在过去的八年中，Cobre）增加了基础科学家可用的资源。这 蛋白质组学/质谱核心，正在开发的生物信息学的核心和中心 申请人将使用生物医学研究（动物设施）。申请人已经开发了 一个现有的现有工具的主动研究计划，并计划增加这些活动 在奖励期间及以后。该提议不可或缺的科学整合的目的是 描述生长激素缺乏对线粒体功能的有益作用的机制， 压力抵抗和健康跨度。我们的研究一直集中在理解以下假设 长活的动物，硫醇代谢的上调会导致更大的保护免受细胞应激。 申请人的工作已经确定，减少生长激素（GH）信号是主要参与者 寿命保证。要测试的全球假设是硫醇代谢在衰老中起关键作用 GH调节该途径的关键组成部分最终导致健康跨度的变化（通过 压力阻力/保护）和寿命。因此，降低的GH信号传导赋予了生物学优势 矮小鼠可以更好地清除有毒的代谢副产品，线粒体功能改变 并增强了寿命。为了进一步解决和定义这一全球假设，申请人计划 阐明GH，硫醇代谢和细胞保护之间的关系：1）直接联系 矮小小鼠的呼吸道和抗氧化活性增强了线粒体GSH和 这些蛋白质的谷胱甘肽化； 2）提供直接证据，表明缺乏GH是负责的 GST系统的底物特异性增强； 3）定义与硫醇代谢相关的变化 饮食改变后的压力耐心和寿命； 4）建立第一个表观基因组学 长寿鼠标的轮廓。确定依赖GH的途径和机制可能表明 治疗性干预措施，以增强压力抗性，延迟衰老，治疗与衰老有关的疾病和 扩展人类的健康状况。