New Genetic Intervention for Healthy Aging

健康老龄化的新基因干预

• 批准号: 6951401
• 负责人: JAMES FLOYD NELSON
• 金额: $ 7.3万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951401
• 关键词: aging; biological models; biological signal transduction; cell proliferation; disease /disorder onset; gene deletion mutation; genetically modified animals; inflammation; insulin; insulin sensitivity /resistance; insulinlike growth factor; laboratory mouse; longevity; phenotype; protein tyrosine phosphatase

DESCRIPTION (provided by applicant): Research Topic 11. Interventions. Reduced insulin/IGF-I signaling is implicated in the extended life span of several mammalian models, including calorie restricted rodents and dwarf mutant mice. Serum insulin and IGF-I levels are markedly reduced and insulin sensitivity for glucose disposal is increased in these models. Mice homozygous for the null mutation of protein tyrosine phosphatase 1B (PTP-1B -/-) closely mimic the insulin/IGF-1 phenotype of calorie restricted and dwarf mice. In addition, they exhibit reduced visceral adiposity, which may be an important mediator of these anti-aging effects, if this metabolic constellation of changes is important in murine longevity, the PTP-1B-/- mouse would seem promising as a new single-gene mutant model of extended longevity. The goal of this proposal is to determine if the PTP-1B-/- mouse is likely to be a longevity mutant, and thus provide the basis for obtaining R01 funding to establish definitively its longevity and healthspan and probe the underlying mechanisms. The Specific Aims are to determine if the PTP-1B -/- mouse: 1. Has an extended median lifespan and exhibits delayed/attenuated age-related pathology. 2. Exhibits reduced cell proliferation and/or inflammatory processes which are hypothesized to contribute to age-related disease and dysfunction. 3. Maintains its insulin/IGF-I/metabolic phenotype throughout adult life. If the results of most or all of these studies are affirmative, they will indicate that nullifying the PTP-1B gene is a genetic intervention with strong potential for retarding aging. These data would enable a R01 application to determine the effect of this genetic intervention on maximal longevity and aging, and to probe its underlying mechanisms. A PTP-1B-/- longevity mutant would also provide a new target for pharmacologic interventions to retard aging.

描述(由申请人提供)：研究主题11.干预措施。胰岛素/IGF-I信号的减少与几种哺乳动物模型的寿命延长有关，包括卡路里限制的啮齿动物和矮小突变小鼠。在这些模型中，血清胰岛素和IGF-I水平显著降低，对葡萄糖处理的胰岛素敏感性增加。蛋白酪氨酸磷酸酶1B(PTP-1B-/-)零突变纯合子小鼠与卡路里限制和矮小小鼠的胰岛素/IGF-1表型非常相似。此外，它们还表现出内脏脂肪减少，这可能是这些抗衰老效果的重要中介，如果这种代谢变化对小鼠的长寿很重要，PTP-1B-/-小鼠似乎有望成为延长寿命的新的单基因突变模型。该提案的目的是确定PTP-1B-/-小鼠是否可能是长寿突变体，从而为获得R01资金以确定其长寿和健康寿命并探索其潜在机制提供基础。 具体目的是确定PTP-1B-/-鼠标： 1.中位寿命延长，并表现出与年龄相关的延迟/减弱的病理。 2.表现出细胞增殖和/或炎症过程减少，这被认为是与年龄相关的疾病和功能障碍的原因之一。 3.成年后维持其胰岛素/IGF-I/代谢表型。 如果大多数或所有这些研究的结果都是肯定的，他们将表明使PTP-1B基因无效是一种具有很强延缓衰老潜力的遗传干预。这些数据将使R01应用程序能够确定这种基因干预对最大寿命和衰老的影响，并探索其潜在机制。PTP-1B-/-长寿突变体也将为延缓衰老的药物干预提供新的靶点。