Sir2 in stress resistance, aging, and DNA repair

描述(由申请人提供)：随着美国老年人比例的上升，与年龄相关的疾病的负担也在增加。衰老是真核生物的普遍特征，但衰老的分子机制仍很不清楚。对衰老的详细分子理解可能会延缓或防止衰老相关的恶化，或许还会延长人类的寿命。Sir2家族成员的过表达在酵母和线虫中都被证明可以延长寿命，哺乳动物Sir2家族成员SIRT1的过表达提高了哺乳动物细胞的抗氧化能力。这种蛋白还可以使P53去乙酰化，降低P53的活性。 这项提案的总体目标是确定Sir2家族成员在抗压中的作用， P53活性的调节，与衰老。这项分析将在小鼠身上进行，需要三个 明确的目标。(1)确定哪些小鼠Sir2家族成员参与氧化 应激抗性，并确定Sir2蛋白在小鼠体内的过度表达是否可以延长 小鼠的寿命。(2)探讨SIRT1与P53的遗传交互作用。(3)明确Sir2家族成员在维持染色体稳定性中的作用。 此申请是为了获得临床科学家发展导师奖(K08)。申请人是医学博士/博士，长期对衰老的基础生物学和住院医师培训感兴趣。 解剖病理学。这项拟议的研究将在哈佛医学院血液研究中心弗雷德里克·艾特博士的实验室进行。申请人之前曾在专门研究酵母的实验室接受过培训。这位候选人的长期目标是领导一个学术研究小组，调查衰老的分子机制和干预措施，以延缓衰老的开始。这笔培训补助金将成为通往这一独立职位的关键桥梁，允许候选人在该国最重要的哺乳动物实验室之一进行研究。

DESCRIPTION (provided by applicant): As the proportion of elderly individuals in the United States rises, the burden of age-associated disease grows. Aging is a universal feature of eukaryotic organisms, yet the molecular mechanisms underlying aging remain largely obscure. A detailed molecular understanding of aging might allow the delay or prevention of aging-associated deterioration and perhaps the extension of human lifespan. Overexpression of Sir2 family members has been shown to extend lifespan in both yeast and C. elegans, and overexpression of a mammalian Sir2 family member, SIRT1, increases oxidative stress resistance in mammalian cells. This protein also can deacetylate p53, reducing p53 activity. The overall goal of this proposal is to define the role of Sir2 family members in stress resistance, modulation of p53 activity, and aging. This analysis will be performed in mice, and entails three specific aims. (1) To define which of the murine Sir2 family members are involved in oxidative stress resistance, and to determine whether overexpression of Sir2 proteins in mice can extend murine lifespan. (2) To evaluate the genetic interaction between SIRT1 and p53. (3) To define the role of Sir2 family members in the maintenance of chromosomal stability. This application is for a Mentored Clinical Scientist Development Award (K08). The applicant is an M.D. /Ph.D. with a longstanding interest in the basic biology of aging, and residency training in Anatomic Pathology. The proposed research will take place in the laboratory of Dr. Frederick AIt at the Center for Blood Research at Harvard Medical School. The applicant previously trained in a laboratory specializing in yeast. The candidate's long-term goal is to direct an academic research group investigating the molecular mechanisms of aging and interventions to delay the onset of senescence. This training grant would serve as a critical bridge to this independent position, by allowing the candidate to study in one of the foremost mammalian labs in the country.