Role of GH on thiol metabolism, stress resistance and aging

项目摘要 本KO 2提案的短期目标是：1）增加用于行为的时间， 完成最近授予的RO 1的实验; 2）完成旨在提高和 丰富申请人在衰老和表观遗传学领域的重点和专业知识。的长期目标 KO 2是有效利用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，特别是在老龄化研究方面 并在未来几年获得更多支持。北方大学的研究环境 达科他州医学与健康科学学院是活跃和不断增长的。两个主要的NIH赠款（INBRE， COBRE）在过去8年中增加了基础科学家可用的资源。的 蛋白质组学/质谱核心，正在开发的生物信息学核心和中心 申请人将使用生物医学研究（动物设施）。申请人已经开发 在UND的一个积极的研究计划与现有的工具，并计划增加这些活动 在获奖期间及以后。这项建议的科学目标是 描述生长激素缺乏对线粒体功能的有益作用的机制， 抗压力和健康寿命。我们的研究一直集中在理解假设， 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，减少的生长激素（GH）信号传导是生长激素缺乏的主要参与者。 长寿保障有待检验的全球假设是，硫醇代谢在衰老中起着关键作用 生长激素调节这一途径的关键成分，最终导致健康寿命的变化（通过 抗应力/保护）和寿命。因此，减少GH信号传导赋予生物学优势， 侏儒小鼠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。为了进一步解决和定义这一总体假设，申请人计划 阐明GH，巯基代谢和细胞保护之间的关系：1）直接连接 在侏儒小鼠中增强呼吸和抗氧化活性以增加线粒体GSH， 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 GST系统的底物特异性增强; 3）定义与GST系统相关的巯基代谢的变化， 改变饮食MET后的抗应激和长寿;以及4）建立第一个表观基因组 一只长寿的老鼠。确定生长激素依赖的途径和机制可能表明， 治疗干预，以增强抗应激能力，延缓衰老，治疗与衰老有关的疾病， 延长人类的健康寿命。

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.