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: 10647777
• 负责人: Judith Campisi
• 金额: $ 57.91万
• 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/10647777
• 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; Early Onset Alzheimer Disease; Fostering; Gene Expression Profile; Genotype; Heterogeneity; Human; Inflammation; Intervention; Knowledge; Laboratories; Malignant Neoplasms; Mass Spectrum Analysis; Metabolic; Metabolism; Microglia; Monitor; Morphology; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organoids; Pathology; Pharmaceutical Preparations; Phenotype; Population; 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; postmitotic; response; senescence; single cell analysis; small molecule; stressor; tau Proteins; 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.

项目摘要 到目前为止，衰老是发展各种神经退行性疾病的最重要驱动因素和风险因素，即 包括阿尔茨海默氏病（AD）和相关痴呆症的常见形式。我们的最新证据 实验室和其他 与年龄有关的疾病，从神经变性到癌症。衰老细胞随着年龄的增长而增加。欠 对于它们复杂的感应相关的秘书表型（SASP），感觉细胞可以具有深远的影响 关于组织结构和功能，并可以促进慢性感染，这是众多年龄的主要贡献者 相关病理。最近，尽管很少有证据表明，感觉细胞可以有助于年龄 相关的神经变性，包括AD和相关痴呆。该计划项目赠款（PPG）的项目1 将深入表征人类和小鼠星形胶质细胞的感应反应，特别是SASP 小胶质细胞和神经元被不同的应激源引起的感官。然后它将确定这些感觉如何 细胞使用同型和异型细胞培养物影响非渗入细胞的功能，并且 终点的范围从差异化功能到代谢状态和转录组的单细胞分析 了解感觉脑细胞群体的异质性。此外，该项目将使用三个 尺寸皮质器官，包括含有野生型基因型的人类细胞的器官 含有含有突变的基因型，这些突变易于早期发作AD和相关痴呆。这些细胞会 源自诱导的多能干细胞。最后，项目1将利用一种新型的转基因鼠标 允许选择性消除感觉细胞的模型，以确定是否以及如何感觉 细胞有时与体内与年龄相关的大脑功能有关。这些协作分析将完成 项目2和3提出的实验并严重依赖于核心B，C和D。 将提供有关大脑中感觉细胞的前所未有的知识，批判性地测试其在驱动AD中的作用 和相关的痴呆症，以及对这些破坏性病理的新干预的开放可能性。