High Resolution Profiling of Senescent Cells in ALS Brain and Spinal Cord

ALS 大脑和脊髓中衰老细胞的高分辨率分析

基本信息

批准号：
10487832
负责人：
Miranda Ethel Orr
金额：
--
依托单位：
W G HEFNER VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-10-01 至 2026-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10487832
关键词：
ALS patients Affect Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Apoptosis Area Autopsy Back Blood Vessels Brain Brain Diseases Cell Aging Cell Death Cell Death Process Cells Cellular Morphology Cellular Stress Central Nervous System Chronic Communities Complex Cytoplasm Data Data Set Deposition Development Diagnosis Disease Disease Progression Environment Family history of Functional disorder Future Goals Health Histologic Human Immunohistochemistry Individual Investigation Lateral Limb structure Link Location Maps Mitochondria Molecular Molecular Profiling Motor Motor Cortex Motor Neurons Movement Muscle Muscle function Nerve Degeneration Nervous System Neurodegenerative Disorders Neuronal Dysfunction Neurons Nuclear Outcome Pathogenicity Pathologic Pathology Pathway interactions Process Proteins RNA Research Research Proposals Resolution Role Site Spinal Cord Spinal Cord Column Spinal Diseases Stress Structure Symptoms Technology Testing Therapeutic Intervention Time Tissue Donors Tissues Transcript Transgenic Mice Validation Veterans analytical method biobank biological adaptation to stress biomarker discovery biomarker validation brain tissue candidate identification candidate marker case control cell injury cell type cellular resilience digital effective therapy experience experimental study extracellular human tissue improved method development military veteran mouse model muscle form neuropathology new therapeutic target novel pharmacologic preservation protein TDP-43 protein expression proteostasis research clinical testing screening senescence single cell analysis stress resilience tau Proteins tau aggregation therapeutic target tissue degeneration transcriptomics

项目摘要

Project Summary/Abstract Regardless of family history, site of onset, and sequence of symptoms and progression, all Amyotrophic Lateral Sclerosis (ALS) patients lose muscle mass as the motor neurons that connect to muscle in limbs to control movement stop working and eventually die. However, there appears to be an extensive delay between initial neuronal dysfunction and physical degeneration. The complex nervous system is maintained, in part, due to cell resiliency to stress in order to maintain function and resist activating cell death processes. Experiments in this proposal will investigate a novel hypothesis: neurons in ALS enter cellular senescence as part of a complicated stress response to avoid active degeneration and cell death. Nonetheless, while this protective mechanism may preserve the physical presence of the cell, senescent cell dysfunction and potentially toxic secretome promotes chronic tissue degeneration over time that facilitates disease progression. Senescence is activated by protein accumulation in other neurodegenerative diseases. Here we will determine whether TDP43 deposition differentially affects the cellular senescence stress response by evaluating postmortem human brain and spinal cord from veteran donors, accessed through the VA ALS Biorepository Brain Bank, with either TDP43 positive or negative neuropathology. To comprehensively investigate neurons and their environment we will utilize GeoMx digital spatial profiling technology. This high resolution, high-content non-destructive analytical method enables the investigation of 100s of proteins at the single cell level while maintaining spatial resolution. This affords the ability to map the data back to the tissue to correlate protein expression differences with cell morphology, location in the tissue, extracellular environment and proximity to vascular and / or other pathologies. The data generated by our research proposal will provided an unprecedented rigor for depth of information on cellular stress in ALS spinal cord and brain. The rich dataset generated through these experiments will open many novel avenues of investigation in ALS and potentially unveil cellular senescence as a new therapeutic target. This is an area desperately in need of development as the majority of ALS patients die, on average, 2-4 years after diagnosis.

项目概要/摘要无论家族史、发病部位、症状和进展的顺序如何，所有肌萎缩侧索硬化症硬化症（ALS）患者失去肌肉质量，因为运动神经元连接到四肢的肌肉来控制运动停止工作并最终死亡。然而，初始之间似乎存在很大的延迟。神经元功能障碍和身体退化。复杂的神经系统的维持部分是由于细胞对压力的弹性，以维持功能并抵抗激活的细胞死亡过程。这方面的实验该提案将研究一个新的假设：ALS 中的神经元进入细胞衰老是复杂的过程的一部分应激反应以避免主动退化和细胞死亡。尽管如此，虽然这种保护机制可能保留细胞的物理存在、衰老细胞功能障碍和潜在有毒的分泌体促进随着时间的推移，慢性组织退化，促进疾病进展。衰老是由蛋白质激活的其他神经退行性疾病中的积累。这里我们要判断TDP43是否沉积通过评估死后的人脑和脊髓，对细胞衰老应激反应产生不同的影响来自退伍军人捐赠者的脐带，通过 VA ALS 生物储存脑库获取，TDP43 呈阳性或阴性神经病理学。为了全面研究神经元及其环境，我们将利用 GeoMx 数字空间剖析技术。这种高分辨率、高内涵的无损分析方法能够在单细胞水平上研究数百种蛋白质，同时保持空间分辨率。这能够将数据映射回组织，将蛋白质表达差异与细胞相关联形态、在组织中的位置、细胞外环境以及与血管和/或其他病理的接近程度。我们的研究计划生成的数据将为以下方面的信息深度提供前所未有的严谨性： ALS 脊髓和大脑中的细胞应激。通过这些实验生成的丰富数据集将打开 ALS 的许多新研究途径，并有可能揭示细胞衰老作为一种新的治疗方法目标。这是一个迫切需要开发的领域，因为大多数 ALS 患者平均死亡 2-4 个月诊断后数年。