The Sir2-p53-IGF link in mammalian life-span control

Sir2-p53-IGF 与哺乳动物寿命控制的联系

• 批准号: 8372123
• 负责人: Eduardo N Chini
• 金额: $ 35.58万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372123
• 关键词: Address; Adult; Affect; Age; Aging; Alleles; Animals; Assisted Reproductive Technology; Biology of Aging; Body Size; Cardiovascular system; Cell Respiration; Cell division; Coupled; Couples; Development; Diabetes Mellitus; Differentiation and Growth; Dose; Ectopic Expression; Embryo; Employee Strikes; Environment; Event; Fetus; Functional disorder; Funding; Gene Targeting; Glean; Grant; Growth; Growth Factor; Health; Human; Individual; Infertility; Insulin; Insulin-Like Growth Factor I; Lead; Length; Life; Life Expectancy; Link; Longevity; Malnutrition; Mammals; Measures; Metabolic; Metabolic Pathway; Metabolism; Molecular; Mouse Strains; Mus; Mutation; Nutrient; Nutritional; Organ; Pathway interactions; Pentosephosphate Pathway; Phenocopy; Phenotype; Protein Isoforms; Protein p53; Proteins; Risk; Somatic Cell; Sorting - Cell Movement; Stem cells; Stress; Testing; Time; adult stem cell; design; detection of nutrient; embryonic stem cell; fetus nutrition; flexibility; genetic element; healthy aging; middle age; mutant; nutrition; receptor; research study; response; trait

DESCRIPTION (provided by applicant): Metabolic reprogramming in response to malnutrition early in life impedes cell division, organ growth, and differentiation, and can lead to permanent growth deficits, as well as decreased life span. The "thrifty phenotype" hypothesis proposes that poor fetal nutrition imposes growth and developmental constraints and changes upon the fetus, which may be considered as achieving metabolic thrift. However, adaptive changes that are beneficial to survival under conditions of poor nutrition may be detrimental under conditions of nutritional abundance and lead to reduced health--‐ and life span. In the second cycle of funding for our grant entitled, ¿The Sir2¿p53¿IGF link in mammalian life span control,¿ we will pursue studies to delineate the molecular mechanism underlying the thrifty phenotype and how metazoan size and life span are coupled. Our hypothesis is that they require the coordinated activity of growth factor driven pathways on the one hand and metabolic pathways on the other, and that what links the two is the activity of the tumor suppressor p53. Specifically, we propose that metabolic flexibility is the function of Delta40p53, an embryonic isoform of p53 that can ¿sense¿ the environment and modulate the activity of full-length p53 on key metabolic target genes in response. The information we glean from the experiments to be undertaken in a second cycle of funding will have important applications in assisted reproductive technology (ART) and in healthy aging. Enormous advances over the past several decades have made it possible for babies to be conceived by and born to couples previously deemed infertile. Emerging evidence indicates, however, that individuals born using ART are prone to decrements in mid-life health associated with cardiovascular and metabolic dysfunction and might be at risk for reduced life expectancy. The overlap in phenotype between humans conceived by ART and experimental animals subjected to nutrient stress early in development is striking and needs to be understood, not just for its own sake, but also because not doing so represents a missed opportunity for designing more rational strategies to optimize the health and well being of all humans. The focus of our new experiments is on events occurring during an early developmental window, when stem cells first arise, that could permanently affect the trajectories of size and life span. We will be using our unique mouse strains with one, two, or three copies of Delta40p53 to develop the notion that events that occur (very) early in life can predispose individuals to changes that occur much later in life, even in old age. This distinct and virtually unexplored field of aging biology has particular relevance to eutherian mammals, including humans. PUBLIC HEALTH RELEVANCE: Paradoxically, robust growth and bigger size are not necessarily good predictors of a long and healthy life span. Despite the obvious significance of this observation, the mechanism that couples longevity and body size is poorly understood. We propose that it is the tumor suppressor p53 that links these two traits by controlling the switch from anaerobic to aerobic metabolism in stem cells.

描述（由申请人提供）：生命早期营养不良的代谢重编程会阻碍细胞分裂、器官生长和分化，并可能导致永久性生长缺陷，以及寿命缩短。“节俭表型”假说认为，胎儿营养不良会对胎儿的生长发育造成限制和改变，这可能被认为是实现了代谢节俭。然而，在营养不良的条件下有利于生存的适应性变化，在营养丰富的条件下可能是有害的，并导致健康状况和寿命的下降。在“哺乳动物寿命控制中的Sir2、p53和IGF链接”项目的第二轮资助中，我们将继续研究节俭表型的分子机制，以及后生动物的大小和寿命是如何耦合的。我们的假设是，它们一方面需要生长因子驱动途径的协调活动，另一方面需要代谢途径的协调活动，而将两者联系起来的是肿瘤抑制因子p53的活动。具体来说，我们提出代谢灵活性是Delta40p53的功能，Delta40p53是p53的一种胚胎亚型，可以感知环境并调节全长p53在关键代谢靶基因上的活性。我们将在第二个资助周期中进行的实验中收集的信息将在辅助生殖技术（ART）和健康老龄化方面有重要应用。在过去的几十年里，巨大的进步使得以前被认为是不育的夫妇怀孕并生下孩子成为可能。然而，新出现的证据表明，出生时使用抗逆转录病毒治疗的人，其中年健康状况容易出现与心血管和代谢功能障碍相关的下降，并可能面临预期寿命缩短的风险。通过抗逆转录病毒技术孕育的人类与发育早期遭受营养压力的实验动物之间的表型重叠是惊人的，需要了解，不仅是为了它本身，而且因为不这样做意味着错过了设计更合理的策略以优化所有人类健康和福祉的机会。我们新实验的重点是发生在早期发育窗口期的事件，当干细胞第一次出现时，这些事件可能永久地影响大小和寿命的轨迹。我们将使用具有一个，两个或三个Delta40p53副本的独特小鼠品系来发展这样一种观念，即生命早期发生的事件可能使个体容易发生在生命后期甚至老年发生的变化。这个明显的和