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.

项目总结 这项KO2提案的短期目标是：1)增加用于进行和 完成最近获奖的RO1的实验；以及2)完成旨在增强和 丰富申请者在老龄化和表观遗传学领域的重点和专业知识。的长期目标是 KO2将有效地利用1)和2)来加强研究生、博士后、 教职员工(目前没有从事老龄领域的工作)和本科生，特别是老龄研究 并在未来几年获得额外的支持。诺斯大学的研究环境 达科他州医学与健康科学学院正在积极发展。美国国立卫生研究院的两大赠款(INBRE， Cobre)在过去的8年里增加了基础科学家可用的资源。这个 正在开发中的生物信息学核心蛋白质组学/质谱学核心和该中心 生物医学研究(动物设施)将由申请者使用。申请人已开发出 在联合国开发计划署利用现有工具积极开展研究计划，并计划增加这些活动 在获奖期间及以后。这项提议所包含的科学目标是 描述生长激素缺乏对线粒体功能有益影响的机制， 抗应激能力和健康寿命。我们的研究一直集中在理解这样的假设上： 长寿的动物，硫醇代谢的上调会导致更好的保护，使其免受细胞压力的影响。 申请人的工作已经确定，减少的生长激素(GH)信号是 长寿保障。有待检验的全球假说是，硫醇代谢在衰老中起关键作用。 生长激素调节这一途径的关键成分，最终导致健康跨度的变化(通过 抗应力/保护)和寿命。因此，GH信号的减少赋予了生物优势 侏儒小鼠能更好地清除有毒代谢副产物，改变线粒体功能 并能延长寿命。为了进一步解决和定义这一全球假设，申请人计划 通过以下途径阐明生长激素、硫醇代谢与细胞保护的关系：1)直接连接 侏儒小鼠呼吸和抗氧化活性增强与线粒体GSH和 这些蛋白质的谷胱甘肽基化；2)提供直接证据，证明缺乏生长激素是导致 底物特异性增强GST系统；3)确定与以下相关的硫醇代谢变化 改变饮食后的抗逆性和寿命；4)建立第一个表观基因组 一只长寿老鼠的简介。确定生长激素依赖的途径和机制可能提示 治疗干预，以增强抗应激能力，延缓衰老，治疗衰老相关疾病和 延长人类的健康寿命。