The Somatotropic Axis and Health Aging: A Search for Mechanisms

生长轴与健康衰老：寻找机制

• 批准号: 7630982
• 负责人: Andrzej Bartke
• 金额: $ 162.22万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7630982
• 关键词: Somatotropic; Axis; Health; Aging; Search

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to identify mechanisms responsible for the effects of growth hormone (GH) signaling on aging and longevity in mammals. Studies conducted by the applicants during the last 10 years, together with results obtained in other laboratories, have provided unequivocal evidence that GH deficiency and GH insensitivity in mice are associated with a marked increase in mean and maximal longevity. Studies of age-sensitive traits and analysis of survival characteristics in GH-deficient and GH-resistant mice indicate that increased longevity of these animals is coupled with and most likely due to a delay and/or deceleration of the process of biological aging. Our collaborative studies and work of other investigators defined a series of mechanisms that might, in principle, link GH signaling with longevity. In the proposed work we will use both well-characterized and novel mouse mutants to probe several of these specific mechanisms. Our aim is to develop a compelling model of the pathway or pathways that connect diminished GH or IGF-I signaling to extended longevity and to relate these pathways to maintenance of cognitive and physical function. The proposed collaborative studies will define the role of liver, adipose tissue and muscle in mediating the effects of GH and IGF-I on age-sensitive traits and longevity; and to elucidate the interactive effects of altered insulin signaling, adipocyte secretory profiles and stress resistance in mediating these effects. Project 1 will relate somatotropic and insulin signaling to stress resistance and aging. Project 2 will produce novel animals lacking the GHR/GHBP gene only in the liver, white adipose tissue or muscle. Project 3 will study mechanisms of stress resistance in fibroblasts and pre-adipocytes and evaluate longevity and age-sensitive traits in novel mutant mice developed in Project 2. Project 4 will characterize pre-adipocyte utilization, characteristics and senescence in mutants with altered GH signaling. Core A will coordinate research, information exchange and communication with Advisory Committee, develop shared data base and provide statistical support. Core B will assess gross and microscopic pathological changes with emphasis on novel mutants developed by Project 2. Improved understanding of the role of somatotropic and insulin signaling in the control of mammalian aging is needed for designing lifestyle and pharmacological interventions to maintain health and functionality during human aging. This information is also needed to develop rational basis for exploring or discouraging the use of human GH as an anti-aging agent. RELEVANCE: Improved understanding of the role of somatotropic and insulin signaling in the control of mammalian aging is needed for designing lifestyle and pharmacological interventions to maintain health and functionality during human aging. This information is also needed to develop rational basis for exploring or discouraging the use of human GH as an anti-aging agent. PRINCIPAL INVESTIGATOR: Dr. Bartke is Professor and Director of Geriatric Medicine in the Department of Internal Medicine at Southern Illinois University School of Medicine. His many years of experience studying the role of GH and IGF-I in mice brings a strong knowledge of endocrinology to this PPG. Dr. Bartke has developed a significant publication record in understanding animal models of aging and how manipulation of the growth hormone/IGF-I axis is related to extended longevity. His laboratory was the first to identify the link between the GH/IGF-1 signaling and longevity in the mouse. Dr. Barke has had substantial administrative experience and is very appropriate to be principal investigator of this PPG. CORE A - ADMINISTRATION; Dr. Andrzej Bartke, Core Leader (CL) DESCRIPTION (provided by applicant): A Program Project of this magnitude will require the coordination of personnel and technical expertise. The main functions of the Administrative Core will be to facilitate communication between the five laboratories involved in the proposed studies. This will entail development and maintenance of a shared database, statistical consultations, the solicitation of input from the Advisory Committee, and organization of an annual meeting of all participants in the Program Project. In addition, Core A will assist in issues related to the budget, distribution of animals and tissues, maintain regular contact with the Project Officer at NIA, and prepare annual progress reports/renewal applications. In Years 04 and 05, Core A will coordinate the planning of future directions of this Program Project and oversee preparation of the application for competing renewal. Five Specific Aims are proposed: 1. To facilitate communication between all participating investigators, all members of the participating laboratories including graduate students and postdoctoral fellows, and investigators and Advisory Committee. 2. To establish and maintain data management system that will facilitate exchange of samples and data between the participating laboratories and maximize utilization of every animal. 3. To provide statistical support and consultations for experimental design and data analysis, and to identify and recommend statistical approaches for combined analysis of data from different Projects/Cores. 4. To provide assistance and oversight of fiscal management of projects and Core B and of exchange of animals, tissues and other samples (plasma, tissue extracts, mRNA or cDNA preparations) between laboratories. 5. To prepare annual progress reports and coordinate preparation of a competing renewal application.

描述(申请人提供)：拟议研究的长期目标是确定生长激素(GH)信号对哺乳动物衰老和长寿的影响的机制。申请者在过去10年中进行的研究，以及在其他实验室获得的结果，提供了明确的证据，表明小鼠的生长激素缺乏和生长激素不敏感与平均寿命和最长寿命的显著增加有关。对生长激素缺乏和抗生长激素小鼠的年龄敏感特征的研究和生存特征的分析表明，这些动物的寿命延长与生物衰老过程的延迟和/或减速有关。我们的合作研究和其他研究人员的工作确定了一系列机制，原则上可能将生长激素信号与长寿联系起来。在拟议的工作中，我们将使用特征良好的和新的小鼠突变来探索这些特定的机制中的几个。我们的目标是开发一个或多个令人信服的途径模型，这些途径将GH或IGF-I信号减弱与延长寿命联系起来，并将这些途径与认知和身体功能的维持联系起来。拟议的合作研究将确定肝脏、脂肪组织和肌肉在GH和IGF-I对年龄敏感性状和寿命的影响中的中介作用；并阐明胰岛素信号改变、脂肪细胞分泌特征和应激抵抗在调节这些影响中的交互作用。项目1将把促生长激素和胰岛素信号与应激抵抗和衰老联系起来。项目2将培育出仅在肝脏、白色脂肪组织或肌肉中缺乏GHR/GHBP基因的新型动物。项目3将研究成纤维细胞和前脂肪细胞的抗应激机制，并评估项目2中开发的新突变小鼠的寿命和年龄敏感特征。项目4将描述生长激素信号改变突变的前脂肪细胞的利用、特征和衰老。核心A将与咨询委员会协调研究、信息交流和沟通，开发共享数据库并提供统计支持。CORE B将评估大体和微观的病理变化，重点是项目2开发的新突变。需要更好地了解促生长激素和胰岛素信号在控制哺乳动物衰老中的作用，以设计生活方式和药物干预措施，以在人类衰老期间保持健康和功能。这些信息也需要开发合理的基础，以探索或不鼓励使用人类生长激素作为抗衰老药物。 相关性：需要更好地了解促生长激素和胰岛素信号在哺乳动物衰老控制中的作用，以设计生活方式和药物干预，以维持人类衰老期间的健康和功能。这些信息也需要开发合理的基础，以探索或不鼓励使用人类生长激素作为抗衰老药物。 主要研究人员：巴特克博士是南伊利诺伊大学医学院内科教授兼老年医学主任。他多年研究GH和IGF-I在小鼠体内的作用的经验为PPG带来了强大的内分泌学知识。Bartke博士在了解衰老的动物模型以及生长激素/IGF-I轴的操纵如何与延长寿命相关方面创造了重要的出版记录。他的实验室是第一个确定GH/IGF-1信号与小鼠寿命之间的联系的实验室。Barke博士有丰富的管理经验，非常适合担任PPG的首席研究员。 核心A-行政管理；Andrzej Bartke博士，核心领导(CL) 描述(由申请者提供)：一个如此规模的项目需要人员和技术专长的协调。行政核心的主要职能将是促进参与拟议研究的五个实验室之间的交流。这将需要开发和维护一个共享数据库，进行统计协商，征求咨询委员会的意见，并组织方案项目所有参与方的年度会议。此外，核心A将协助处理与预算、动物和组织分配有关的问题，与国家臭氧机构的项目官员保持定期联系，并编写年度进度报告/续签申请。在04年和05年，核心A将协调本计划项目未来方向的规划，并监督竞争续签申请的准备工作。提出了五个具体目标：1.为促进所有参与研究人员、包括研究生和博士后研究员在内的参与实验室所有成员以及调查人员和咨询委员会之间的沟通。2.建立和维护数据管理系统，以促进参与实验室之间的样本和数据交换，并最大限度地利用每一只动物。3.为实验设计和数据分析提供统计支持和咨询，确定和建议对不同项目/核心数据进行联合分析的统计方法。4.协助和监督项目和核心B的财务管理以及实验室之间动物、组织和其他样本(血浆、组织提取物、信使核糖核酸或脱氧核糖核酸制剂)的交换。5.编写年度进度报告，并协调编写相互竞争的续展申请。