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，年龄相关疾病的负担也在增加。衰老是真核生物的一个普遍特征，但衰老的分子机制仍不清楚。对衰老的详细分子理解可能会延迟或预防与衰老相关的恶化，并可能延长人类寿命。Sir 2家族成员的过表达已被证明可以延长酵母和C. elegans，以及哺乳动物Sir 2家族成员SIRT 1的过表达增加哺乳动物细胞中的氧化应激抗性。这种蛋白质还可以使p53脱乙酰化，降低p53活性。 该提案的总体目标是确定Sir 2家族成员在抗应激中的作用， p53活性的调节和衰老。该分析将在小鼠中进行，并且需要三个 具体目标。(1)为了确定哪些鼠Sir 2家族成员参与氧化应激， 应激抗性，并确定小鼠中Sir 2蛋白的过表达是否可以延长 小鼠寿命。(2)目的探讨SIRT 1与p53基因的相互作用。(3)明确Sir 2家族成员在维持染色体稳定性中的作用。 此应用程序是一个指导临床科学家发展奖（K 08）。申请人是一名医学博士。/博士长期以来对衰老的基础生物学感兴趣， 解剖病理学拟议的研究将在哈佛医学院血液研究中心Frederick AIt博士的实验室进行。申请人以前在酵母专业实验室接受过培训。候选人的长期目标是指导一个学术研究小组，研究衰老的分子机制和延缓衰老的干预措施。这项培训补助金将作为通往这一独立职位的重要桥梁，允许候选人在该国最重要的哺乳动物实验室之一学习。

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.