Novel models for longevity research

长寿研究的新模型

• 批准号: 8243150
• 负责人: CHRISTIAN SELL
• 金额: $ 19.31万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243150
• 关键词: Address; Aging; Animal Model; Animals; Biochemical; Biological Models; Bone Growth; Brain; Caenorhabditis elegans; Cardiac Myosins; Cause of Death; Climacteric; Development; Drosophila melanogaster; Elderly; Exhibits; Genetic; Gerontology; Growth; Growth Hormone Receptor; Hormones; Human; Insulin; Insulin-Like Growth Factor I; Longevity; Malignant Neoplasms; Mammals; Mediating; Metabolism; Modeling; Mus; Muscle; Mutation; Organ; Pathology; Play; Prealbumin; Production; Receptor Signaling; Relative (related person); Research; Role; Signal Pathway; Signal Transduction; Somatomedins; Somatotropin; Therapeutic; Therapeutic Uses; Thinking; Tissues; Work; attenuation; base; bone; cost; end of life; field study; glucose metabolism; growth hormone deficiency; improved; insight; mouse model; novel; pituitary gland development; promoter; tool

DESCRIPTION (provided by applicant): Among the most important issues in biogerontology today is an understanding of the mechanisms that underlie lifespan extension associated with reduced activity in the insulin/IGF-I signaling pathway. Whereas single mutations in the IGF-I receptor and signaling pathways impart lifespan extension in Caenorhabditis elegans and Drosophila melanogaster, the most robust examples of lifespan extension in mammals are associated with reductions in both IGF-I and growth hormone. Mouse models exhibiting deficiency in pituitary development or growth hormone production and/or signaling show decreased IGF-I levels and a dramatic increase in lifespan. Against a backdrop of growth hormone deficiency, however, it is impossible to attribute the effect on lifespan in these animals solely to reductions in IGF-I, excluding a potentially distinct role for growth hormone in mammalian lifespan modulation. Mouse lines which exhibit reduced IGF-I signaling show much smaller increases in lifespan suggesting that IGF-I suppression alone may not be sufficient to produce the robust lifespan extension seen in animals which lack both growth hormone and IGF-I. However, current models do not provide the tools necessary to define the roles that IGF-I and growth hormone play in modulating longevity in mammals. We propose to create novel mouse models, exhibiting growth hormone independent production of IGF-I. We will perform a characterization of these mice in terms of IGF-I production, development, metabolism, bone growth and lifespan. If we find a major influence of GH on longevity independent of IGF-I, the results of these studies would pave the way for a paradigm shift in our thinking regarding the influence of IGF-I and longevity. PUBLIC HEALTH RELEVANCE: The work proposed in this application will create new mouse line that do not produce growth hormone but will produce one of the primary targets of growth hormone, known as the Insulin-like growth factor type 1. These mice will be used to evaluate the relative contribution of these hormones to late life changes and lifespan. The studies will provide insight into potential therapeutic uses for these hormones in the elderly.

描述（由申请人提供）：当今老年医学中最重要的问题之一是理解与胰岛素/IGF-I信号通路活性降低相关的寿命延长的机制。尽管IGF-I受体和信号通路中的单突变赋予秀丽隐杆线虫和黑腹果蝇寿命延长，但哺乳动物寿命延长的最有力的例子与IGF-I和生长激素的减少有关。表现出垂体发育或生长激素产生和/或信号传导缺陷的小鼠模型显示IGF-I水平降低和寿命显著增加。然而，在生长激素缺乏的背景下，不可能将对这些动物寿命的影响仅仅归因于IGF-I的减少，排除生长激素在哺乳动物寿命调节中的潜在独特作用。表现出降低的IGF-I信号传导的小鼠系显示出小得多的寿命增加，这表明单独的IGF-I抑制可能不足以产生在缺乏生长激素和IGF-I的动物中观察到的稳健的寿命延长。然而，目前的模型没有提供必要的工具来定义IGF-I和生长激素在调节哺乳动物寿命中的作用。我们建议建立新的小鼠模型，表现出生长激素非依赖性IGF-I的生产。我们将在IGF-I产生、发育、代谢、骨生长和寿命方面对这些小鼠进行表征。如果我们发现GH对寿命的主要影响独立于IGF-I，这些研究的结果将为我们关于IGF-I和寿命影响的思维范式转变铺平道路。 公共卫生相关性：本申请中提出的工作将创建新的小鼠品系，其不产生生长激素，但将产生生长激素的主要靶点之一，称为胰岛素样生长因子1型。这些小鼠将用于评估这些激素对晚年变化和寿命的相对贡献。这些研究将为这些激素在老年人中的潜在治疗用途提供深入了解。