Cell Autonomous and Non-Autonomous Mechanisms of Aging

描述(由申请人提供)：这项名为“细胞自主和非自主衰老机制”的计划项目资助的目标是研究自发的、随机的损伤驱动衰老的机制。这个计划试图挑战当前的观念，即随机的细胞损伤，特别是DNA损伤，通过触发细胞程序性死亡或衰老，通过以细胞自主为主的机制促进衰老。虽然众所周知，在应对高剂量的遗传毒性应激时，细胞可以分泌衰老相关因子，这些因子对邻近细胞具有旁分泌作用，但还没有人证实非细胞自主事件在体内响应生理水平的内源性DNA损伤而推动衰老。拟议的实验将解决一个衰老模型，其中年龄相关的随机损伤的积累，包括DNA损伤，通过细胞自主和非自主途径驱动衰老。该计划项目由三个高度整合的项目组成。项目1(Laura Niedernhofer)将研究DNA损伤的细胞自主和非自主影响，测量氧化DNA损伤、细胞衰老、ROS水平和与衰老相关的病理。项目2(Paul Robbins)将研究核因子-KB的细胞自主和非自主角色，核因子-KB是一种在应对细胞损伤和压力时激活的转录因子，在随年龄增长而驱动衰老、ROS和氧化DNA损伤方面发挥作用。最后，项目3(Johnny Huard)将分析与年龄相关的干细胞功能丧失所涉及的细胞自主和非自主途径，以及确定功能性成人干细胞分泌的延长寿命和健康寿命的因素。所有项目将使用自然衰老小鼠和加速衰老小鼠模型的组织和细胞，包括组织中ERCC1缺失的小鼠-专门影响DNA损伤的速度，一次一个组织。这些项目将得到四个核心的支持，A)行政(Paul Robbins)；B)老鼠模型(Laura Niedernhofer)；C)成像(Simon Watkins)和D)蛋白质组学(Nathan Yates)。

DESCRIPTION (provided by applicant): The goal of this Program Project Grant, entitled "Cell Autonomous and Non-autonomous Mechanisms of Aging" is to examine the mechanisms by which spontaneous, stochastic damage drives aging. This Program seeks to challenge the current notion that stochastic cellular damage, in particular, DNA damage promotes aging through a predominantly cell-autonomous mechanism by triggering programmed cell death or senescence. Although it is well-established that in response to high doses of genotoxic stress cells can secrete senescence-associated factors, which have a paracrine effect on neighboring cells, no one has established that non-cell autonomous events drive aging in response to physiological levels of endogenous DNA damage in vivo. The proposed experiments will address a model of aging where age-dependent accumulation of stochastic damage, including DNA damage, drives aging through both cell autonomous and non-autonomous pathways. This Program Project is comprised of three highly integrated projects. Project 1 (Laura Niedernhofer) will examine the cell autonomous and non-autonomous effects of DNA damage, measuring oxidative DNA damage, cellular senescence, ROS levels and aging-related pathology. Project 2 (Paul Robbins) will examine the cell autonomous and non-autonomous roles of NF-KB, a transcription factor activated in response to cellular damage and stress, in driving senescence, ROS and oxidative DNA damage with aging. Finally, Project 3 (Johnny Huard) will analyze the cell autonomous and non-autonomous pathways involved in age-related loss of stem cell function, as well as identify the factors secreted by functional adult stem cells that extend lifespan and healthspan. All projects will use tissues and cells from naturally aged mice and mouse models of accelerated aging, including mice in which ERCC1 is deleted tissue-specifically to affect the rate of DNA damage one tissue at a time. The projects will be supported by four cores, A) Administrative (Paul Robbins); B) Mouse Models (Laura Niedernhofer); C) Imaging (Simon Watkins) and D) Proteomics (Nathan Yates).