Mechanisms of Differential Cellular Protection

差异细胞保护机制

• 批准号: 8816023
• 负责人: VALTER D. LONGO
• 金额: $ 43.96万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816023
• 关键词: Affect; Aging; Alkylating Agents; Allografting; Apoptosis; Biological Models; Biology of Aging; Bone Marrow; Bone Marrow Cells; Brain; Breast Cancer Cell; Bypass; Cell Aging; Cell division; Cells; Chronic; Cisplatin; Collaborations; DNA; DNA Damage; Development; Disease; Dose; Doxorubicin; Drug Targeting; GRP78 gene; Gene Expression Profile; Generations; Genes; Genetic; Genetic Models; Gerontology; Glucose; Growth Hormone Receptor; Heart; Hematopoietic; Injection of therapeutic agent; Instruction; Insulin-Like Growth Factor I; Interphase Cell; Intervention; Knowledge; Laboratories; Lead; Life; Light; Link; Liver; Longevity; Lung; MAPK14 gene; Mammalian Cell; Measurement; Mediating; Modeling; Molecular; Monitor; Motor Activity; Mus; Mutation; Organism; Oxidants; Oxidative Stress; Paraquat; Pathway interactions; Pharmaceutical Preparations; Prevention; Principal Investigator; Proteins; Reactive Oxygen Species; Regulation; Research; Resistance; Ribosomal Protein S6 Kinase; Role; Saccharomyces cerevisiae; Serum; Short-Term Memory; Signaling Protein; Somatotropin; Starvation; Stem cells; Stress; Substantia nigra structure; System; Testing; Tissues; Toxin; Tumor Volume; Work; Yeasts; age related; base; biological adaptation to stress; cancer cell; cell injury; chemotherapy; copper zinc superoxide dismutase; cytotoxicity; dietary restriction; genetic manipulation; improved; inhibitor/antagonist; malignant breast neoplasm; mouse model; mutant; novel; older patient; overexpression; oxidative damage; receptor; repaired; research study; response; stem; subcutaneous; synergism; tool; transcription factor; tumor; tumor progression

Research in the major genetic model systems has revealed a strong and consistent association between dietary restriction, mutations that extend life span, and resistance to multiple stresses. Here we propose to investigate the mechanisms of aging with focus on starvation-dependent protection against oxidative damage and life span. We propose to continue our work to establish which combination of treatments and genetic manipulations causes the maximum resistance to toxins and identify the underiying mechanisms with focus on ER stress. We will continue and expand our mammalian cell and mouse studies to determine the role of short-term starvation on cellular senescence and aging in murine models and identify the mechanisms of starvation-dependent protection. We will also test the hypothesis that pathways analogous to those identified in yeast can protect normal but not cells with constitutively active pro-aging pathways (cancer cells) against oxidative damage and chemotherapy (Differential Stress Resistance, DSR) and study the mechanisms involved. Because older subjects are particularly sensitive to toxins, we will study DSR in young and old mice to identify interventions that can protect old organisms against cytotoxicity. The collaborations with Cohen and Lee will continue to introduce novel ideas, approaches, and research tools to our laboratory and provide the synergism necessary to accelerate our research. This collaborative biogerontology-based approach has the potential to identify new genetic pathways and mechanisms relevant to the basic biology of aging but also interventions that can be applied to the development of improved treatments and prevention of age-related diseases. RELEVANCE (See instructions): Research on age-related diseases focuses primarily on the damaged cells or tissues affected by the disease. Here we propose to take a biogerontology-based approach to instead focus on the mechanisms of protection of all the healthy cells ofthe organism. These studies will help identify strategies, genetic pathways and drug targets to protect the organism against the age-dependent damage and diseases caused by endogenous as well as exogenous toxins.

对主要遗传模型系统的研究表明， 饮食限制、延长寿命的突变以及对多种压力的抵抗力。在此我们建议 研究衰老机制，重点关注饥饿依赖性的氧化保护 损坏和寿命。我们建议继续努力确定治疗和治疗的组合 基因操作导致对毒素的最大抵抗力并确定其潜在机制 关注 ER 压力。我们将继续并扩大我们的哺乳动物细胞和小鼠研究，以确定 短期饥饿对小鼠模型细胞衰老的作用并确定 饥饿依赖性保护机制。我们还将检验以下假设：路径类似于 在酵母中发现的那些可以保护正常细胞，但不能保护具有持续活跃的促衰老途径的细胞 （癌细胞）对抗氧化损伤和化疗（差异应激抵抗，DSR）和研究 所涉及的机制。由于老年受试者对毒素特别敏感，我们将研究 DSR 对年轻和年老的小鼠进行研究，以确定可以保护年老生物体免受细胞毒性的干预措施。这 与科恩和李的合作将继续引入新颖的想法、方法和研究工具 我们的实验室并提供加速我们研究所需的协同作用。此次合作 基于生物老年学的方法有可能确定新的相关遗传途径和机制 不仅涉及衰老的基础生物学，而且还涉及可用于开发改进的干预措施 治疗和预防与年龄有关的疾病。 相关性（参见说明）： 与年龄相关的疾病的研究主要集中在受年龄影响的受损细胞或组织上。 疾病。在这里，我们建议采取基于生物老年学的方法来关注 保护有机体的所有健康细胞。这些研究将有助于确定策略、遗传 保护机体免受年龄依赖性损伤和疾病的途径和药物靶点 受内源性和外源性毒素的影响。