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：
10044065
负责人：
Morgan Elyse Levine
金额：
$ 41.2万
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/10044065
关键词：
ATAC-seq 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 Animal Model Astrocytes Automobile Driving Autopsy Behavior Binding Biological Assay Biological Markers Biology Biophysics Brain Brain region Cell Aging Cells Characteristics Chemicals Coupled DNA Methylation Data Development Disease Endothelial Cells Environment Epigenetic Process Exhibits Exposure to Fatty Acids Fibroblasts Genes Genetic Genetic Transcription Genomic Instability Gold 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 Neuraxis Neuroglia Neurologic Oncogene Activation Pathogenesis Pathologic Pathway Analysis Patients Peripheral Phenotype Physiological Play Radiation Role Sampling Severity of illness Signal Transduction Slice Solubility Techniques Testing Therapeutic Tissues Validation abeta oligomer age related base biological systems biomarker development biophysical techniques brain cell cell type disorder control experimental study human tissue in vivo irradiation molecular modeling molecular phenotype nervous system disorder neuroinflammation novel novel marker oligodendrocyte progenitor reconstitution response senescence simulation single-cell RNA sequencing stem cells stressor structured data 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 (Abo), 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. Abo is thought to bind membrane proteins and subsequently signal downstream aggregation of related amyloids such as tau. In fact, the presence of endogenous Abo 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 Abo 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.

项目摘要细胞感应是衰老的主要标志之一，描述了细胞分裂的突然无法分裂。衰老细胞通常会随着物理和化学胁迫的响应（基因组不稳定性，端粒损耗，照射等），尽管这些压力源与神经系统疾病之间的重叠此类重叠由于阿尔茨海默氏病（AD）目前尚不清楚。经常利用的感应的体外实验压力源，例如过氧化氢或辐射，可能与年龄有关诸如AD之类的疾病。此外，在体外观察到的感应表型可能未完成模型对于动态生物系统中发生的情况。可溶性淀粉样蛋白β低聚物（ABO）是AD中的重要标志，已显示出潜在的诱导与原纤维AB相比，各种脑细胞类型和环境中的衰老。 Abo被认为可以约束膜蛋白和随后对相关淀粉样蛋白（如tau）的下游聚集信号。实际上，内源性ABO的存在是AD模型中疾病严重程度最强的指标之一，生物体，表明AD和细胞感应之间的联系才开始探索。为了研究这种关联，我们建议将黄金标准技术和单细胞OMICS相结合数据是为了定义敏感的异质遗传和表观遗传学特征，这是一个明显的其诱导类型的功能。这样做还将产生强大的特征和感应的生物标志物可用于人体组织的病理表型的脑细胞。这些措施也将允许为了比较不同的感觉行为，以帮助识别最类似于类似于的实验室衍生的淀粉样蛋白患者来源的结构。我们将评估多个实验室衍生的ABO结构，包括从脂质位于大脑的主要溶解区域。观察将与溶液生物物理学实验和分子建模，为每个诱导剂提供类似的结构数据类型。综上内源性诱导剂与实验室重构的诱导剂之间的重叠，并强调AD 风险受细胞感应调节。