Role of GH on thiol metabolism, stress resistance and aging

描述(由申请人提供)：这项K02提案的短期目标是：1)增加用于进行和完成最近授予的R01的实验的时间；以及2)完成旨在增强和丰富申请人在老龄化和表观遗传学领域的专注和专业知识的练习。K02的长期目标是有效地利用1)和2)加强对研究生、博士后、教师(目前没有从事老龄领域的工作)和本科生的培训，特别是在老龄研究方面，并在未来几年获得额外的支持。北达科他大学医学院和健康科学学院的研究环境很活跃，而且还在不断增长。在过去的8年里，美国国立卫生研究院的两项主要拨款(INBRE和Cobre)增加了基础科学家可用的资源。申请者将使用蛋白质组学/质谱学核心，这是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)。申请人利用现有的工具在联合国开发计划署制定了一项积极的研究方案，并计划在授标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。我们的研究一直专注于理解这一假设，即在长寿动物中，硫醇代谢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，减少生长激素(GH)信号是长寿保证的主要参与者。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，最终导致健康寿命(通过应激抵抗/保护)和寿命的变化。因此，生长激素信号的减少为矮小小鼠提供了生物学优势，导致更好地清除有毒代谢副产物，改变线粒体功能，并延长寿命。为了进一步解决和定义这一全球假说，申请人计划通过以下方式阐明生长激素、硫醇代谢和细胞保护之间的关系：1)直接将矮小鼠增强的呼吸和抗氧化活动与这些蛋白质的线粒体GSH和谷胱甘肽基化联系起来；2)提供直接证据，证明缺乏GH是底物特异性GST系统增强的原因；3)定义改变饮食后硫醇代谢的变化，与抗应激和长寿有关；以及4)建立长寿小鼠的第一个表观基因组谱。确定生长激素依赖的途径和机制可能会建议进行治疗干预，以增强人类的抗应激能力，延缓衰老，治疗与衰老相关的疾病，并延长人类的健康寿命。 公共卫生相关性：这项K02提案旨在为研究和培训提供受保护的时间，并丰富申请者在老龄化和表观遗传学领域的科学知识。这段受保护的时间将用于成功完成旨在确定生长激素对两个长寿小鼠品系Ames侏儒和生长激素受体基因敲除小鼠的抗应激和寿命相关过程的影响的实验。确定生长激素依赖的途径和机制可能会为延缓衰老、治疗衰老相关疾病和延长人类寿命提供潜在的治疗干预措施。

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.