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: 8149871
• 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/8149871
• 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; 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; public health relevance; research study; respiratory; stressor; tool

DESCRIPTION (provided by applicant): The short term objectives of this K02 proposal are: 1) to increase the time devoted to conduct and complete experiments of a recently awarded R01; 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 K02 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. PUBLIC HEALTH RELEVANCE: This K02 proposal is designed to provide protected time for research and training and to enrich the applicants' science in the areas of aging and epigenetics. This protected time will be used towards the successful completion of experiments designed to determine the influence of growth hormone on processes related to stress resistance and longevity using two long-living mouse strains, Ames dwarf and growth hormone receptor knockout mice. Determining GH-dependent pathways and mechanisms may suggest potential therapeutic interventions to delay aging, treat aging-related disorders and extend life span in humans.

描述（由申请人提供）：本K 02提案的短期目标是：1）增加用于进行和完成最近授予的R 01实验的时间; 2）完成旨在增强和丰富申请人在衰老和表观遗传学领域的重点和专业知识的练习。K 02的长期目标是有效地利用1）和2）加强研究生，博士后，教师（目前不在老龄化领域工作）和本科生的培训，特别是在老龄化研究方面，并在未来几年获得额外的支持。北达科他州大学医学与健康科学学院的研究环境活跃且不断发展。在过去的8年里，NIH的两项主要赠款（INBRE，COBRE）增加了基础科学家可用的资源。申请人将使用蛋白质组学/质谱核心（正在开发的生物信息学核心）和生物医学研究中心（动物设施）。申请人已经在UND开发了一个积极的研究计划，并计划在获奖期间及以后增加这些活动。这项建议的科学目标是描述生长激素缺乏对线粒体功能，抗应激能力和健康寿命的有益影响的机制。我们的研究一直集中在理解这一假设，即在长寿动物中，硫醇代谢的上调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）信号传导是长寿保证的主要参与者。有待检验的全球假设是，硫醇代谢在衰老中起着关键作用，GH调节该途径的关键组分，最终导致健康寿命（通过抗应激/保护）和寿命的变化。因此，减少GH信号传递赋予侏儒小鼠生物学优势，导致更好地清除有毒代谢副产物，改变线粒体功能和延长寿命。为了进一步阐述和定义这一总体假设，申请人计划通过以下方式阐明GH、硫醇代谢和细胞保护之间的关系：1）将侏儒小鼠中增强的呼吸和抗氧化活性与这些蛋白质的线粒体GSH和谷胱甘肽化增加直接联系起来; 2）提供GH缺乏导致GST系统的底物特异性增强的直接证据; 3）定义改变饮食MET后与应激抗性和寿命相关的硫醇代谢的变化;以及4）建立长寿小鼠的第一个表观基因组谱。确定生长激素依赖性途径和机制可能会建议治疗干预，以提高抗应激能力，延缓衰老，治疗衰老相关疾病和延长人类的健康寿命。 公共卫生相关性：该K 02提案旨在为研究和培训提供受保护的时间，并丰富申请人在衰老和表观遗传学领域的科学。该保护时间将用于成功完成实验，该实验旨在使用两种长寿小鼠品系，艾姆斯侏儒和生长激素受体敲除小鼠，确定生长激素对与应激抗性和寿命相关的过程的影响。确定GH依赖性途径和机制可能表明潜在的治疗干预措施，以延缓衰老，治疗衰老相关疾病和延长人类寿命。