Cell Autonomous and Non-Autonomous Mechanisms of Aging

细胞自主和非自主衰老机制

• 批准号: 8913519
• 负责人: Paul D. Robbins
• 金额: $ 15万
• 依托单位: SCRIPPS FLORIDA
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913519
• 关键词: Accounting; Address; Affect; Aging; Animals; Apoptosis; Attenuated; Automobile Driving; Biological Models; Cell Aging; Cell physiology; Cells; Correlative Study; DNA Damage; DNA Repair; Databases; Disease; Distant; Doctor of Veterinary Medicine; Dose; ERCC1 gene; Event; Failure; Florida; Genotoxic Stress; Goals; Grant; Health; Histocompatibility Testing; Image; Imaging Techniques; In Vitro; Letters; Longevity; Maps; Measures; Methods; Modeling; Molecular; Mus; Organ; Organ failure; Organism; Oxidative Stress; Parabiosis; Pathologist; Pathology; Pathway interactions; Phenotype; Physiological; Piper; Plague; Play; Production; Program Research Project Grants; Proteins; Proteomics; Reagent; Resources; Role; Signal Transduction; Stem cells; Stress; Supporting Cell; Symptoms; System; Testing; Therapeutic; Time; Tissues; Universities; Washington; activating transcription factor; adult stem cell; age related; aged; cell type; data exchange; design; experience; in vivo; mouse model; mutant; novel strategies; operation; oxidative DNA damage; paracrine; programs; release factor; research study; response; senescence

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）：本计划项目资助的目标，题为“细胞自主和非自主老化机制”是检查自发的，随机损伤驱动老化的机制。该计划旨在挑战目前的概念，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的主要细胞自主机制促进衰老。虽然它是公认的，在响应高剂量的遗传毒性应激细胞可以分泌衰老相关因子，这对邻近细胞具有旁分泌作用，没有人已经确定，非细胞自主事件驱动衰老响应生理水平的内源性DNA损伤在体内。拟议的实验将解决一个老化模型，其中年龄依赖性随机损伤（包括DNA损伤）的积累通过细胞自主和非自主途径驱动衰老。该项目由三个高度综合的项目组成。项目1（Laura Niedernhofer）将研究DNA损伤的细胞自主和非自主效应，测量氧化DNA损伤，细胞衰老，ROS水平和衰老相关的病理学。项目2（Paul Robbins）将研究NF-κ B的细胞自主和非自主作用，NF-κ B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DNA损伤中的作用。最后，项目3（Johnny Huard）将分析与年龄相关的干细胞功能丧失相关的细胞自主和非自主途径，并确定功能性成体干细胞分泌的延长寿命和健康的因子。所有项目都将使用来自自然衰老小鼠和加速衰老小鼠模型的组织和细胞，包括ERCC 1被组织特异性删除的小鼠，以一次影响一个组织的DNA损伤率。这些项目将由四个核心支持，A）行政（Paul Robbins）; B）小鼠模型（Laura Niedernhofer）; C）成像（Simon Watkins）和D）蛋白质组学（Nathan Yates）。