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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目总结