The Role of p16INK4 in Mammalian Aging

p16INK4 在哺乳动物衰老中的作用

• 批准号: 9095219
• 负责人: NORMAN E SHARPLESS
• 金额: $ 33.52万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095219
• 关键词: Address; Affect; Age; Aging; Alleles; Animals; Appearance; Atherosclerosis; Attenuated; Beta Cell; Biological Assay; Biological Markers; CD8B1 gene; CDKN2A gene; Caloric Restriction; Cell Aging; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Cellular Stress; Chronic; Cytotoxic Chemotherapy; DNA Damage; Disease; Epigenetic Process; Epitopes; Exhibits; Exposure to; Failure; Funding; Genetic; Genetic Polymorphism; Genetic study; Glaucoma; Growth; HIV Infections; Health; Hematopoietic; Hematopoietic stem cells; Histones; Human; Human Genetics; Immune; Inflammatory; Knowledge; Life; Malignant Neoplasms; Mammals; Measures; Modeling; Mus; Muscle satellite cell; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Oncogenic; Pancreas; Pathology; Phenotype; Physiology; Play; Process; Reporter; Reporting; Repression; Resistance; Risk; Role; Single Nucleotide Polymorphism; Stem cells; Stress; Structure of beta Cell of islet; Support System; T-Lymphocyte; Testing; Tissues; Tobacco use; Toxin; Transferase; Transgenic Animals; Tumor Suppressor Proteins; Work; age effect; age related; aged; anti aging; cell age; cell injury; cell type; cytokine; fitness; functional decline; genome wide association study; immunogenic; in vivo; nerve stem cell; novel; physical inactivity; prevent; regenerative; repaired; response; self renewing cell; self-renewal; senescence; stem; tobacco exposure; tumorigenesis

 DESCRIPTION (provided by applicant): Work from our lab and others has established that expression of the p16INK4a tumor suppressor mechanism plays a critical role in mammalian aging. The expression of p16INK4a in the setting of certain cellular stresses and tissue pathology clearly plays a beneficial role in limiting important age-associated conditions associated with excess proliferation such as cancer and atherosclerosis. The activation of p16INK4a throughout life, however, is associated with the accumulation of cells that have undergone senescence, a permanent form of growth arrest, which is also associated with the elaboration of pathogenic, pro-inflammatory cytokines. Therefore, the beneficial cancer-preventing expression of p16INK4a compromises some aspects of organismal fitness with aging by limiting the regeneration and repair of certain self-renewing compartments. During the prior ten years of this proposal, our group, with collaborators, has provided significant evidence for this model. In 2004, we showed that p16INK4a is a faithful biomarker of mammalian aging. In 2006, we showed that p16INK4a-deficient animals demonstrate a resistance to some aging phenotypes in pancreatic ß-cells, neural stem cells and hematopoietic stem cells, while transgenic animals expressing excess p16INK4a demonstrate an accelerated functional decline with aging in these compartments. In 2009, we developed an approach to measuring p16INK4a expression with aging in humans, and employed this assay to show the age-promoting effects of tobacco use, physical inactivity, chronic HIV infection, and cytotoxic chemotherapy in people. We also identified a highly common polymorphism in humans that strongly affects p16INK4a expression and is associated with atherosclerotic disease. In 2011, we showed an important effect of p16INK4a expression on the physiology of aging B- vs. T-lymphocytes, and provided an explanation for how p16INK4a expression limits atherosclerotic disease. Finally, in 2013, we reported in Cell that p16INK4a expression with aging does not predict malignancy risk in mice, and showed that locus activation results in vivo from cell-non-autonomous mechanisms. 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 employ novel reporter and p16CRE alleles to study whether p16INK4a expressing cells are always senescent in vivo. In specific aim II, we will examine the effects of depleting p16INK4a-expressing cells on tumorigenesis and aging using a genetic or immune approach. In specific aim III, we will examine the effects of alterations in the cellular epigenetic state on expression f p16INK4a and somatic stem cell function with aging. Through these approaches, we will further delineate the contribution of p16INK4a expression and cellular senescence to 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证实，p16INK4a 肿瘤抑制机制的表达在哺乳动物衰老中发挥着关键作用。 p16INK4a 在某些细胞应激和组织病理学环境中的表达显然在限制与过度增殖相关的重要年龄相关疾病（如癌症和动脉粥样硬化）方面发挥着有益作用。然而，p16INK4a 在整个生命过程中的激活与经历衰老的细胞的积累有关，衰老是一种永久性的生长停滞形式，这也与致病性促炎细胞因子的产生有关。因此，p16INK4a 的有益防癌表达通过限制某些自我更新区室的再生和修复，损害了机体健康与衰老的某些方面。在该提案提出的前十年中，我们的团队与合作者为该模型提供了重要的证据。 2004 年，我们证明 p16INK4a 是哺乳动物衰老的可靠生物标志物。 2006年，我们发现p16INK4a缺陷的动物表现出对胰腺β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的转基因动物则表现出这些区室的功能随着衰老而加速衰退。 2009 年，我们开发了一种测量人类衰老过程中 p16INK4a 表达的方法，并利用该测定法来显示吸烟、缺乏身体活动、慢性 HIV 感染和细胞毒性化疗对人类的促衰老作用。我们还发现了人类中高度常见的多态性，该多态性强烈影响 p16INK4a 表达并与动脉粥样硬化疾病相关。 2011 年，我们证明了 p16INK4a 表达对衰老 B 淋巴细胞与 T 淋巴细胞生理学的重要影响，并为 p16INK4a 表达如何限制动脉粥样硬化疾病提供了解释。最后，2013 年，我们在《Cell》杂志上报道，p16INK4a 随衰老的表达并不能预测小鼠的恶性肿瘤风险，并表明体内基因座激活是细胞非自主机制的结果。在更新该提案时，我们寻求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，我们采用新的报告基因和 p16CRE 等位基因来研究 p16INK4a 表达细胞在体内是否总是衰老。在具体目标 II 中，我们将使用遗传或免疫方法研究耗尽 p16INK4a 表达细胞对肿瘤发生和衰老的影响。在具体目标 III 中，我们将研究细胞表观遗传状态的改变对 f p16INK4a 表达和衰老过程中成体干细胞功能的影响。通过这些方法，我们将进一步阐明 p16INK4a 表达和细胞衰老对哺乳动物衰老的贡献。