The Role of p16INK4a in Mammalian Aging

描述（由申请人提供）：我们实验室和其他实验室的工作已经确定，p16INK4a肿瘤抑制机制的有益抗癌功能也对哺乳动物衰老有贡献。在这个模型中，与年龄相关的p16INK4a表达通过限制某些自我更新区室的再生和修复而损害了生物体的适应性。为了支持这一假设，我们实验室和合作者的最新数据表明，p16INK4a缺陷的动物表现出对胰腺细胞、神经干细胞和造血干细胞中某些衰老表型的抵抗力，而表达过量p16INK4a的转基因动物表现出随着这些细胞的衰老而加速的功能衰退。该模型的其他支持来自最近的人类全基因组和候选关联研究，这些研究将编码p16INK4a的CDKN2a基因座附近的单核苷酸多态性与人类年龄相关疾病如虚弱，2型糖尿病和动脉粥样硬化疾病（心肌梗死，缺血性中风和腹主动脉瘤）联系起来。在更新这一建议时，我们试图扩展这些先前的观察结果，以进一步增强我们对p16INK4a如何影响哺乳动物衰老的理解。在具体目标I中，我们建议使用我们实验室产生的新p16INK4a条件等位基因进一步确定p16INK4a在胰腺细胞衰老中的作用。在具体目标II中，我们将进一步研究p16INK4a在使用种系和条件性p16INK4a缺陷小鼠的动脉粥样硬化小鼠模型中的作用。在具体目标III和IV中，我们将重点关注p16INK4a在淋巴细胞老化中的作用。在目的III中，我们将表征在这些组织中携带p16INK4a体细胞失活的小鼠中的T细胞和B细胞的数量和功能。在目的IV中，我们将研究p16INK4a在人类T细胞中的表达与衰老和暴露于促衰老刺激物如细胞毒性化疗后。通过这些方法，我们将进一步描述p16INK4a对年龄相关表型的贡献，如2型糖尿病，动脉粥样硬化和免疫功能障碍。公共卫生相关性：衰老的某些方面是由于组织修复和再生能力下降造成的。在某些细胞类型中，这种组织再生能力的下降部分是由细胞内在抗癌机制的激活引起的。人类遗传学研究表明，这一过程在动脉粥样硬化和2型糖尿病等衰老相关疾病中尤为重要。在这项工作中，我们使用人类和小鼠的实验系统来研究抗癌机制在衰老中的作用。

DESCRIPTION (provided by applicant): Work, from our lab and others, has established that the beneficial, anti-cancer function of the p16INK4a tumor suppressor mechanism also untowardly contributes to mammalian aging. In this model, the age-associated expression of p16INK4a compromises organismal fitness by limiting the regeneration and repair of certain self-renewing compartments. In support of this hypothesis, recent data from our lab and collaborators has shown that p16INK4a-deficient animals demonstrate a resistance to certain aging phenotypes in pancreatic -cells, neural stem cells and hematopoietic stem cells, while transgenic animals expressing excess p16INK4a demonstrate an accelerated functional decline with aging in these compartments. Additional support for this model has come from recent human genome-wide and candidate association studies which have linked single nucleotide polymorphisms near the CDKN2a locus, which encodes p16INK4a, to human age-associated conditions such as frailty, type 2 diabetes and atherosclerotic disease (myocardial infarction, ischemic stroke and abdominal aortic aneurysm). In the renewal of this proposal, we seek to extend these prior observations to further enhance our understanding of how p16INK4a influences mammalian aging. In specific aim I, we propose to further define the role of p16INK4a in pancreatic -cell aging using a novel p16INK4a-conditional allele generated in our lab. In specific aim II, we will further study the role of p16INK4a in a murine model of atherosclerosis using germline and conditional p16INK4a-deficient mice. In specific aims III and IV, we will focus on the role of p16INK4a in lymphocyte aging. In aim III, we will characterize T- and B-cell number and function in mice harboring somatic inactivation of p16INK4a in these tissues. In aim IV, we will study the expression of p16INK4a in human T-cells with aging and after exposure to age-promoting stimuli such as cytotoxic chemotherapy. Through these approaches, we will further delineate the contribution of p16INK4a to age-associated phenotypes such as type 2 diabetes, atherosclerosis and immune dysfunction in humans in mice. PUBLIC HEALTH RELEVANCE: Some aspects of aging result from a decline in the ability of tissues to repair and regenerate. This decline in tissue regenerative capacity is in part caused, in some cell types, by activation of the cell's intrinsic anti-cancer machinery. Human genetic studies have suggested this process is of particular importance in aging-related diseases such as atherosclerosis and type 2 diabetes. In this work, we use experimental systems in humans and mice to investigate the role of anti-cancer mechanisms in aging.