Cell competition as a novel aspect of cellular senescence during aging

细胞竞争是衰老过程中细胞衰老的一个新方面

• 批准号: 10266822
• 负责人: Judith Campisi
• 金额: $ 29.1万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266822
• 关键词: Affect; Age; Aging; Behavior; Biology; Candidate Disease Gene; Cell Aging; Cell Polarity; Cell Proliferation; Cell Survival; Cells; Cellular Stress; Coin; Complex; Coupled; Data; Development; Disease; Drosophila genus; Embryonic Development; Environment; Epithelial Cells; Event; Fibroblasts; Gene Proteins; Genotype; Goals; Homeostasis; Human; Inflammatory; Laboratories; Light; Malignant Neoplasms; Mediating; Metabolic; Methods; Molecular; Mutation; Nutrient; Oncogene Activation; Organism; Pathology; Phenotype; Process; Proteome; Proteomics; Radiation; Research; Ribosomal Proteins; Role; Stimulus; Techniques; Testing; Time; Tissues; Transgenic Mice; Tumor Suppressor Proteins; age related; aged; c-myc Proto-Oncogenes; cell killing; cell type; chemotherapy; exhaustion; genotoxicity; healthspan; high throughput screening; improved; mouse model; mutant; novel; novel drug class; novel therapeutics; renal epithelium; response; senescence; single-cell RNA sequencing; stressor; transcriptome; transcriptomics

PROJECT SUMMARY A critical level at which aging is regulated is the cellular responses to molecular events, which in turn alter the tissue and systemic milieu. Understanding cell fate decisions that occur in response to endogenous and exogenous insults that cause aging offers opportunities to develop novel therapies for age-related phenotypes and pathologies. One important cell fate that drives aging is cellular senescence: an essentially irreversible arrest of cell proliferation coupled to a complex senescence-associated secretory phenotype (SASP). Senescent cells increases with age in most tissues. These cells can drive a surprisingly diverse array of aging phenotypes and diseases, largely through the SASP. Moreover, eliminating senescent cells, using either transgenic mouse models or a new class of drugs termed senolytics, can help maintain homeostasis in aged or damaged tissues, and postpone or ameliorate many age-related pathologies. In this proposal, we will characterize a novel aspect of cellular senescence, cell competition, to determine how it contributes to aging. Cell competition is a process by which neighboring (winner) cells detect and remove suboptimal (loser) cells by killing and engulfing them. Our preliminary data show that several senescence-inducing stimuli allow a subset of senescent cells to acquire winner status, allowing them to actively kill and engulf a subset of neighboring non-senescent cells. This killing is transient and coincides with the onset of the pro-inflammatory SASP. We propose that this early transient killing of non-senescent neighbors is required for the long-term survival of pro- inflammatory senescent cells during aging. It is possible that a subset of senescent cells acquires winner status to avoid elimination and/or acquire nutrients (by engulfment) for survival. Deciphering the mechanisms of cell competition in the context of cellular senescence is essential to understand many processes in biology, ranging from embryogenesis to cancer. Using unbiased high throughput techniques such as proteomics and single cell transcriptomics, we plan to determine the molecular events that regulate cell competition by early senescent cells. Further, investigating these processes will open new opportunities for eliminating pro- inflammatory senescent cells before they can drive pathology.

项目摘要 调节衰老的临界水平是对分子事件的细胞反应，这反过来改变了 组织和系统环境。了解响应内源性和内源性和 导致衰老的外在侮辱提供了开发与年龄相关表型的新疗法的机会 和病理。驱动衰老的一种重要细胞命运是细胞衰老：本质上是不可逆的 结合复杂衰老相关的分泌表型（SASP）的细胞增殖的停滞。 衰老细胞在大多数组织中随着年龄的增长而增加。这些细胞可以驱动出令人惊讶的多样化的衰老 表型和疾病主要通过SASP。此外，消除衰老细胞，使用这两个细胞 转基因小鼠模型或一种称为塞溶剂剂的新药物可以帮助维持老年或 损坏的组织，推迟或改善许多与年龄有关的病理。在此提案中，我们将 表征细胞衰老，细胞竞争的新方面，以确定其对衰老的贡献。 细胞竞争是一个相邻（获胜者）细胞检测并通过次优（失败）细胞的过程 杀死并吞噬他们。我们的初步数据表明，几种引起衰老的刺激允许子集 衰老细胞获得获胜者身份，使他们积极杀死并吞噬了邻近的一部分 非元素细胞。这种杀戮是短暂的，与促炎SASP的发作相吻合。我们 提出，这种早期的非年代邻居的早期短暂杀害是需要长期生存的 衰老过程中炎症性衰老细胞。一部分衰老细胞可能获得赢家 避免消除和/或获取营养（通过吞噬）生存的状态。破译机制 在细胞衰老的背景下，细胞竞争对于了解生物学的许多过程至关重要 从胚胎发生到癌症。使用公正的高通量技术，例如蛋白质组学和 单细胞转录组学，我们计划确定通过早期调节细胞竞争的分子事件 衰老细胞。此外，调查这些过程将为消除亲计划的新机会 炎症性衰老细胞可以驱动病理。