Cellular senescence and cell fate/interactions as drivers of Alzheimer's and age-related dementias

细胞衰老和细胞命运/相互作用是阿尔茨海默氏症和年龄相关性痴呆的驱动因素

• 批准号: 10187412
• 负责人: Judith Campisi
• 金额: $ 58.14万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10187412
• 关键词: 3-Dimensional; 3xTg-AD mouse; Adopted; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Astrocytes; Automobile Driving; Autopsy; Behavioral; Biological; Brain; Cell Aging; Cell Communication; Cell Culture Techniques; Cell Nucleus; Cell Proliferation; Cells; Chronic; Coculture Techniques; Collaborations; Complement; Complex; Data; Dementia; Development; Differentiation Antigens; Disease; Fostering; Gene Expression Profile; Genotype; Helper-Inducer T-Lymphocyte; Heterogeneity; Human; Inflammation; Intervention; Knowledge; Laboratories; Malignant Neoplasms; Mass Spectrum Analysis; Metabolic; Metabolism; Microglia; Mitotic; Monitor; Morphology; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organoids; Pathology; Pharmaceutical Preparations; Phenotype; Population; Presenile Alzheimer Dementia; Program Research Project Grants; Proteins; Proteomics; Risk Factors; Role; Slice; Stimulus; Stress; Structure; Testing; Tissues; Transgenic Mice; abeta oligomer; age group; age related; age related neurodegeneration; aged; brain cell; brain tissue; cell type; exosome; experimental study; in vivo; induced pluripotent stem cell; metabolome; metabolomics; mouse model; novel; response; senescence; single cell analysis; small molecule; stressor; tau aggregation; transcriptome

PROJECT SUMMARY Aging is by far the most important driver and risk factor for developing a variety of neurodegenerative diseases, including the common forms of Alzheimer’s disease (AD) and related dementias. Recent evidence from our laboratory and others indicate that a cell fate termed cellular senescence is an effective driver of a diverse group of age-related diseases ranging from neurodegeneration to cancer. Senescent cells increase with age. Owing to their complex senescence-associated secretory phenotype (SASP), senescent cells can have profound effects on tissue structure and function, and can foster chronic inflammation, a major contributor to numerous age- related pathologies. There is also recent, albeit sparse, evidence that senescent cells can contribute to age- related neurodegeneration, including AD and related dementias. Project 1 of this Program Project Grant (PPG) will characterize in depth the senescence responses, particularly the SASPs, of human and mouse astrocytes, microglia and neurons induced to senescent by different stressors. It will then determine how these senescent cells affect the function of non-senescent cells, using both homotypic and heterotypic cell cultures, and a variety of endpoints ranging from differentiated functions to metabolic state and single cell analyses of transcriptomes to understand the heterogeneity of senescent brain cell populations. In addition, the Project will use three dimensional cortical organoids, including organoids containing human cells with wild-type genotypes and those with genotypes containing mutations that predispose to early onset AD and related dementias. These cells will be derived from induced pluripotent stem cells. Finally, Project 1 will take advantage of a novel transgenic mouse model that permits the selective elimination of senescent cells in order to determine whether and how senescent cells are causally related to age-related brain function in vivo. These collaborative analyses will complement experiments proposed by Projects 2 and 3 and rely heavily on Cores B, C and D. Together, these experiments will provide unprecedented knowledge about senescent cells in the brain, critically test their role in driving AD and related dementias, and open possibilities for novel interventions into these devasting pathologies.

项目概要 迄今为止，衰老是多种神经退行性疾病最重要的驱动因素和风险因素， 包括常见形式的阿尔茨海默病 (AD) 和相关痴呆症。我们的最新证据 实验室和其他人表明，称为细胞衰老的细胞命运是多样化群体的有效驱动因素 与年龄相关的疾病，从神经退行性疾病到癌症。衰老细胞随着年龄的增长而增加。欠 衰老细胞因其复杂的衰老相关分泌表型（SASP）而产生深远的影响 组织结构和功能，并可促进慢性炎症，这是许多老年痴呆症的主要原因 相关病理。最近也有证据表明，衰老细胞可能会导致年龄增长，尽管证据很少。 相关的神经退行性疾病，包括 AD 和相关的痴呆症。本计划项目1 项目补助金（PPG） 将深入表征人类和小鼠星形胶质细胞的衰老反应，特别是 SASP， 不同应激源诱导小胶质细胞和神经元衰老。然后它将决定这些衰老的 细胞影响非衰老细胞的功能，使用同型和异型细胞培养物以及各种 终点范围从分化功能到代谢状态以及转录组的单细胞分析 了解衰老脑细胞群的异质性。此外，该项目还将使用三 立体皮质类器官，包括含有野生型基因型人类细胞的类器官以及那些 基因型含有易患早发性 AD 和相关痴呆症的突变。这些细胞将 源自诱导多能干细胞。最后，项目 1 将利用新型转基因小鼠 允许选择性消除衰老细胞以确定衰老细胞是否以及如何衰老的模型 细胞与体内年龄相关的脑功能存在因果关系。这些协作分析将补充 项目 2 和 3 提出的实验严重依赖于核心 B、C 和 D。这些实验一起 将提供有关大脑衰老细胞的前所未有的知识，严格测试它们在驱动 AD 中的作用 和相关的痴呆症，并为对这些破坏性病症进行新的干预措施提供了可能性。