Age and Gender Differences in Apoptosis and Stem Cells

细胞凋亡和干细胞的年龄和性别差异

• 批准号: 6825383
• 负责人: Dorothy Eileen Vatner
• 金额: $ 31.49万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6825383
• 关键词: Macaca fascicularis; adenylate cyclase; age difference; aging; apoptosis; cell differentiation; cell proliferation; disease /disorder model; enzyme inhibitors; gender difference; gene targeting; genetic transcription; genetically modified animals; heart ventricle; hyperplasia; laboratory mouse; muscle cells; myocardial ischemia /hypoxia; myocardium disorder; postmenopause; stem cells; subtraction hybridization; terminal nick end labeling; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): The overall hypothesis of this application is that the aging female heart engages several compensatory mechanisms to prevent the development of a cardiomyopathic state. One important mechanism involves protection against apoptosis. In contrast, the aging male heart, which exhibits more apoptosis than the aging female heart, invokes a proliferation of myocytes and increased stem cells to help offset the consequences of the enhanced apoptosis. The two major unique features of this proposal are: 1 ) the use of the primate model of aging, and 2) examination of gender differences. Indeed, the majority of research in aging has been conducted in rodent models or in humans with associated diseases of aging, e.g., diabetes or atherosclerosis. The primate model is unique because it is phylogenetically closer to humans, yet does not have these associated diseases of aging. This is relevant to this proposal, which relies heavily on genomics and proteomics, where there are many similarities between non-human primates and humans. In addition, most prior work in this field has concentrated on male animals or human subjects. Accordingly, the initial themes in this proposal include examination of two hypotheses: 1) There is greater myocyte hyperplasia including increased stem cells in the aging male monkey heart, potentially as a compensatory mechanism in response to the enhanced apoptosis; 2) There are major gender differences in the development of apoptosis in the aging monkey heart. In the post-menopausal female monkey, where there is less apoptosis with aging than in the male heart, there is agene and protein program of cell survival. These mechanisms also protect the aging female heart more than the aging male heart in response to myocardial ischemia. An additional component of this proposal is to examine two novel molecular mechanisms protecting apoptosis identified in the aging monkey heart, which are: 1) downregulation of adenylyl cyclase type 5 and 2) upregulation of XIAP. These mechanisms will be examined in genetically engineered mouse models, which we hypothesize will exhibit protection from apoptosis and the cardiomyopathy of aging resulting in enhanced longevity. In summary, this proposal will provide new conceptual information on gender differences with regard to compensatory adaptive mechanisms in the aging heart in a novel primate model.

描述（由申请人提供）：本申请的总体假设是，老年女性心脏参与几种代偿机制，以防止心肌病状态的发展。 一个重要的机制涉及对细胞凋亡的保护。 相比之下，衰老的男性心脏比衰老的女性心脏表现出更多的细胞凋亡，引起肌细胞增殖和干细胞增加，以帮助抵消增强的细胞凋亡的后果。 这项建议的两个主要特点是：1）使用灵长类动物模型的老化，和2）性别差异的检查。 事实上，大多数关于衰老的研究都是在啮齿动物模型或患有衰老相关疾病的人类中进行的，例如，糖尿病或动脉粥样硬化。灵长类动物模型是独特的，因为它在遗传学上更接近人类，但没有这些相关的衰老疾病。 这与本提案相关，该提案严重依赖基因组学和蛋白质组学，其中非人类灵长类动物与人类之间有许多相似之处。 此外，该领域的大多数先前工作集中在雄性动物或人类受试者上。 因此，本提案中的初始主题包括对两种假设的检查：1）在衰老雄性猴心脏中存在更大的肌细胞增生，包括干细胞增加，可能作为响应于增强的细胞凋亡的补偿机制; 2）衰老猴心脏中细胞凋亡的发展存在主要的性别差异。 在绝经后的雌性猴子中，随着年龄的增长，细胞凋亡比雄性猴子少，这是细胞存活的基因和蛋白程序。 这些机制在应对心肌缺血时也比老年男性心脏更能保护老年女性心脏。 该提议的另一个组成部分是检查在衰老猴心脏中鉴定的保护细胞凋亡的两种新的分子机制，它们是：1）腺苷酸环化酶5型的下调和2）XIAP的上调。 这些机制将在基因工程小鼠模型中进行研究，我们假设这些模型将显示出对细胞凋亡和衰老心肌病的保护，从而延长寿命。 总之，这一建议将提供新的概念信息性别差异方面的补偿适应机制在老龄化的心脏在一个新的灵长类动物模型。