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AMYLOIDOGENIC INDUCTION OF CELLULAR SENESCENCE IN ALZHEIMER'S DISEASE

阿尔茨海默病中细胞衰老的淀粉样诱导

基本信息

批准号：
10672372
负责人：
ANDREW D. MIRANKER
金额：
$ 41.49万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672372
关键词：
ATAC-seq Adipocytes Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Astrocytes Automobile Driving Autopsy Behavior Binding Biological Assay Biological Markers Biology Biophysics Brain Brain region Cell Aging Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Central Nervous System Characteristics Chemicals Coupled DNA Methylation Data Development Disease Disparate Endothelial Cells Environment Epigenetic Process Exhibits Experimental Models Exposure to Fatty Acids Fibroblasts Genetic Genetic Transcription Genomic Instability Grant Human Hydrogen Peroxide In Vitro Inflammatory Ionizing radiation Link Lipids Machine Learning Measurement Measures Membrane Proteins Mesenchymal Stem Cells Microglia Modeling Molecular Molecular Profiling Nerve Degeneration Neuroglia Neurologic Oncogene Activation Organism Pathogenesis Pathologic Pathway Analysis Patients Peripheral Phenotype Physiological Play Radiation Regional Disease Role Sampling Severity of illness Signal Transduction Slice Solubility Techniques Testing Therapeutic Tissues Validation abeta oligomer age related biological systems biomarker development biophysical techniques brain cell cell type experimental study gene network human tissue in vivo irradiation molecular modeling molecular phenotype nervous system disorder neuroinflammation neuropathology novel novel marker oligodendrocyte progenitor reconstitution response senescence simulation single-cell RNA sequencing stem cells stressor tau Proteins telomere therapeutic target

项目摘要

PROJECT SUMMARY Cellular senescence, one of the major hallmarks of aging, describes the sudden inability for cells to divide. Senescent cells often accumulate with age, in response to physical and chemical stressors (genomic instability, telomere attrition, irradiation, etc.), though the overlap between these stressors and neurological diseases such as Alzheimer’s Disease (AD) is currently unknown. In-vitro experiments of senescence often utilize contrived stressors such as hydrogen peroxide or radiation, that may not be physiologically relevant for age-related diseases such as AD. Furthermore, the senescence phenotypes observed in vitro are likely not complete models for what is occurring in dynamic biological systems. Soluble amyloid-beta oligomers (Aβo), an important hallmark in AD, have been shown to potently induce senescence in a variety of brain cell types and environments, in contrast to fibrillar Ab. Aβo is thought to bind membrane proteins and subsequently signal downstream aggregation of related amyloids such as tau. In fact, the presence of endogenous Aβo is one of the strongest indicators of disease severity in AD models and organisms, suggesting a link between AD and cellular senescence that is only beginning to be explored. In order to study this association, we propose to combine gold-standard techniques and single-cell omics data in order to define heterogenous genetic and epigenetic signatures of senescence that are distinctly a function of their induction type. Doing so will also produce robust signatures and biomarkers of senescence in brain cells that can be utilized for the pathological phenotyping of human tissues. These measures will also allow for the comparison of disparate senescent behaviors to help identify lab-derived amyloids that best resemble patient-derived constructs. We will evaluate multiple lab-derived Aβo constructs, including those stabilized from lipids located in predominantly diseased regions of the brain. Observations would be synergistically coupled with solution biophysics experiments and molecular modeling, providing analogous structural data for each inducer type. Taken together, these measurements will uniquely profile senescence in brain cells, define the degree of overlap between endogenous senescence inducers and those reconstituted in the lab, and highlighting how AD risk is modulated by cellular senescence.

项目总结

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Defining the Neuropathological Aggresome across in Silico, in Vitro, and ex Vivo Experiments.

DOI：
10.1021/acs.jpcb.0c09193
发表时间：
2021-03-04
期刊：
The journal of physical chemistry. B
影响因子：
0
作者：
Gomes GN;Levine ZA
通讯作者：
Levine ZA

Tick tock, tick tock: Mouse culture and tissue aging captured by an epigenetic clock.

DOI：
10.1111/acel.13553
发表时间：
2022-03
期刊：
Aging cell
影响因子：
7.8
作者：
Minteer C;Morselli M;Meer M;Cao J;Higgins-Chen A;Lang SM;Pellegrini M;Yan Q;Levine ME
通讯作者：
Levine ME