Uncoupling Age- Versus Cognitive-Related Cellular Senescence in Alzheimer's Disease

阿尔茨海默病中年龄与认知相关的细胞衰老的解耦

• 批准号: 10454751
• 负责人: Sean Curtis Bendall
• 金额: $ 37.8万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/10454751
• 关键词: Address; Affect; African Green Monkey; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; American; Antibodies; Archives; Astrocytes; Automobile Driving; Axon; Biochemical; Blood Vessels; Brain; Brain Diseases; Brain imaging; Brain region; Cell Aging; Cells; Cerebellum; Cerebrum; Cessation of life; Clinical; Clinical Pathology; Cognitive; Communities; Complex; Data; Dementia; Dendrites; Disasters; Disease; Disease Marker; Family; Funding; Gold; Health Policy; Healthcare Systems; Heterogeneity; Hippocampus (Brain); Human; Image; Immune; Impaired cognition; Inferior; Infrastructure; Injury; Label; Lobule; Machine Learning; Maps; Measurement; Metabolic; Metals; Microglia; Mitotic; Modeling; Molecular and Cellular Biology; Multiplexed Ion Beam Imaging; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Oligodendroglia; Parietal; Pathology; Pattern; Phenotype; Policy Maker; Population; Predisposition; Process; Proteins; Proteomics; Public Health; Research; Research Personnel; Resistance; Risk Factors; Running; Sampling; Senile Plaques; Severities; Specimen; Synapses; Technology; Time; Tissues; Tonsil; Validation; abeta accumulation; age related; aged; aging brain; area striata; brain tissue; cell injury; cohort; collaborative approach; deep learning; disability; entorhinal cortex; healthy aging; high dimensionality; human model; imaging platform; innovation; insight; learning strategy; loss of function; middle age; mild cognitive impairment; mind control; molecular imaging; molecular phenotype; nanometer resolution; nanoscale; neuronal cell body; neuropathology; nonhuman primate; normal aging; novel; novel imaging technique; predictive signature; prevent; programs; release factor; response; senescence; shared database; stressor; tau Proteins; therapeutic target; vervet

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is a leading cause of disability and death in the US and a major global public health problem. Time is running short if we wish to avert a global public health disaster with untold suffering, disruption of families, and severe challenges to health care systems and economies. Effectual solutions will come only from innovative research. While aging is the biggest risk factor for developing AD, it is unclear to what extent normal aging is distinct from AD and which age-related factors drive disease. Senescence is a homeostatic response, which aims to prevent the propagation of these damaged cells while they remain viable and metabolically active. Senescent-like phenotypes have been described in neurons despite neurons being post-mitotic cells and these cells may release factors that trigger senescence in surrounding glia. Senescent glia and senescent-like neurons increase in the brain with age and are thought to contribute to the loss of function associated with aging and age-related diseases like AD. Our application, entitled “Uncoupling Age- Versus Cognitive-Related Cellular Senescence in Alzheimer's Disease,” is highly responsive to the objectives outlined in the RFA-AG-20-025, by leveraging an innovative molecular imaging platform we invented at Stanford; multiplexed ion beam imaging (MIBI), in order to uncouple age- from cognitive decline-related cellular senescence. MIBI enables us to quantify, with low nanometer resolution, high-dimensional, protein-level expression patterns, single-cell (neuro/immune) interactions, and spatial localization of senescence- and AD- relevant molecules (Aim 1) in a model of healthy aging (Aim 2) and well-characterized cases of AD related cognitive impairment (Aim 3). Importantly, MIBI allows all of this to be accomplished in archival FFPE material, thus allowing retrospective analysis on a variety of existing cohorts. By creating in-depth, phenotypic cellular signatures with spatial context from our unique aging and cognitive cohorts, we will be able to provide insight for modifiable factors promoting cognitive decline by filtering those specifically associated with aging alone. In this research program, collaborative expertise in clinical neuropathology and cognitive decline, technological advancements in imaging, biochemical/molecular and cellular biology, and machine learning analytics converge in this proposed research program to address the spatio-cellular (neuro/immune, senescent) heterogeneity in non-human primate (NHP) and human models of healthy aging and AD brains. Furthermore, it will be synergistic to, and draw on expertise developed in existing infrastructure to image and organize AD clinical pathology (R01AG056287, R01AG057915, MPIs: SC Bendall, RM Angelo, TJ Montine) as well as the NIA-funded 90+ UCI cohort, control material housed in the Stanford ADRC, and NHP specimens (P50 AG047366 co-I: TJ Montine). We will reveal cellular senescent phenotypes that differentiate AD from normal age-associated senescence.

项目摘要/摘要 阿尔茨海默氏病（AD）是美国残疾和死亡的主要原因，也是全球主要的公共卫生 问题。如果我们想避免遭受不为人知的痛苦，时间很短， 家庭的破坏，以及对医疗保健系统和经济的严重挑战。有效的解决方案将 仅来自创新研究。尽管衰老是开发广告的最大风险因素，但尚不清楚 正常衰老的程度与AD不同，哪些与年龄相关的因素驱动疾病。衰老是 稳态反应，旨在防止这些受损细胞的传播，而它们保持生存 并代谢活跃。在神经元目的地神经元中已经描述了衰老样的表型 有线后细胞和这些细胞可能会释放因周围神经胶质触发感受的因素。衰老 神经胶质和感觉状神经元随着年龄的增长而增加，被认为会导致丧失 与衰老和与年龄相关的疾病（如AD）相关的功能。我们的申请名为“未偶联年龄 - 在阿尔茨海默氏病中与认知相关的细胞衰老与认知相关的细胞衰老，“对目标的反应很高 在RFA-AG-20-025中概述，通过利用我们发明的创新分子成像平台 斯坦福多路复用离子束成像（MIBI），以使年龄与认知衰落相关的细胞不合时宜 感应。 MIBI使我们能够以低纳米分辨率（高维，蛋白质水平）进行量化 表达模式，单细胞（神经/免疫）相互作用以及感应和AD-的空间定位 相关分子（AIM 1）在健康衰老模型（AIM 2）和AD相关的良好特征案例中 认知障碍（目标3）。重要的是，MIBI允许所有这些都可以在档案中的ffpe材料中完成， 因此，可以对各种现有队列进行回顾性分析。通过创建深入的表型细胞 来自我们独特的衰老和认知队列的空间上下文的签名，我们将能够提供见解 对于可修改的因素，通过过滤与单独衰老有关的因素来促进认知能力下降。 该研究计划，临床神经病理学和认知能力下降方面的协作专业知识，技术 成像，生化/分子和细胞生物学以及机器学习分析的进步 在该建议的研究计划中汇聚，以解决空间细胞（神经/免疫，感觉） 非人类灵长类动物（NHP）的异质性和健康衰老和大脑的人类模型。此外， 它将与现有基础架构中开发的专业知识协同作用，以形象和组织广告 临床病理学（R01AG056287，R01AG057915，MPIS：SC Bendall，RM Angelo，TJ Montine）以及 NIA资助的90+ UCI队列，位于Stanford ADRC中的控制材料和NHP标本（P50 AG047366 CO-I：TJ Montine）。我们将揭示分化AD与正常的细胞感觉表型 与年龄相关的感应。