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 调节衰老的一个关键水平是细胞对分子事件的反应，这反过来又改变了衰老的机制。 组织和全身环境。了解细胞命运的决定，发生在响应内源性和 导致衰老的外源性损伤为开发针对年龄相关表型的新疗法提供了机会 和病理学。一个重要的细胞命运，驱动老化是细胞衰老：一个基本上不可逆转的 细胞增殖停滞与复杂衰老相关分泌表型（SASP）偶联。 在大多数组织中，衰老细胞随着年龄的增长而增加。这些细胞可以导致一系列令人惊讶的衰老 表型和疾病，主要是通过SASP。此外，消除衰老细胞，使用 转基因小鼠模型或一类称为senolytics的新药，可以帮助维持老年人的体内平衡， 损伤的组织，并推迟或改善许多与年龄有关的病理。在本提案中，我们将 表征细胞衰老的一个新方面，细胞竞争，以确定它如何有助于衰老。 小区竞争是相邻（赢家）小区通过以下方式检测并移除次优（失败）小区的过程： 杀死并吞噬它们我们的初步数据表明，几种衰老诱导刺激允许一个子集 衰老细胞获得赢家地位，使它们能够积极杀死和吞噬邻近细胞的子集。 非衰老细胞。这种杀伤是短暂的，与促炎性SASP的发作一致。我们 提出，这种早期短暂杀死非衰老的邻居是需要长期生存的亲， 衰老过程中的炎性衰老细胞。衰老细胞的一个亚群可能获得了赢家， 状态，以避免消除和/或获得营养（通过吞噬）生存。破译机制 细胞衰老背景下的细胞竞争对于理解生物学中的许多过程至关重要， 从胚胎发育到癌症使用无偏的高通量技术，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控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核武器提供新的机会。 炎症性衰老细胞才能导致病理学改变