Cell Autonomous and Non-Autonomous Mechanisms of Aging

细胞自主和非自主衰老机制

• 批准号: 9782441
• 负责人: Paul D. Robbins
• 金额: $ 14.07万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9782441
• 关键词: Cell; Autonomous; Non; Mechanisms; Aging

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).

描述（由申请人提供）：该计划项目赠款的目标，标题为“衰老的细胞自主和非自治机制”是检查自发，随机损害驱动衰老的机制。该计划试图挑战当前的观念，即随机细胞损伤，特别是DNA损伤通过触发程序性细胞死亡或衰老来促进主要的细胞自主机制促进衰老。尽管有良好的建立良好的是，对高剂量的遗传毒性应激细胞可以分泌与衰老相关的因素，这些因素对邻近细胞具有旁分泌作用，但没有人确定非细胞自主事件在体内内源性DNA损伤的生理水平上驱动衰老。提出的实验将解决衰老模型，其中随机损伤的年龄依赖性积累（包括DNA损伤）通过细胞自主和非自治途径驱动衰老。该计划项目由三个高度集成的项目组成。项目1（Laura Niedernhofer）将检查DNA损伤的细胞自主和非自主效应，测量氧化DNA损伤，细胞衰老，ROS水平和与衰老相关的病理学。项目2（Paul Robbins）将检查NF-KB的细胞自主和非自主作用，NF-KB是一种响应细胞损伤和压力而激活的转录因子，在驱动衰老，ROS和氧化性DNA损伤中随着衰老而衰老。最后，项目3（Johnny Huard）将分析与年龄相关的干细胞功能丧失涉及的细胞自主和非自主途径，并确定功能性成年干细胞分泌的因素，这些因素延伸了寿命和HealthSpan。所有项目都将使用来自自然老化的小鼠的组织和细胞以及加速衰老的小鼠模型，其中包括将ERCC1特定删除的小鼠，以一次影响DNA损伤的速率一次。这些项目将得到四个核心的支持，a）行政（保罗·罗宾斯）； B）小鼠模型（Laura Niedernhofer）； C）成像（Simon Watkins）和D）蛋白质组学（Nathan Yates）。