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

• 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
• 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' 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

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.

项目摘要/摘要 不论家族病史，发作部位以及症状和进展的顺序，所有肌萎缩性侧向 硬化症（ALS）患者失去肌肉质量，作为与四肢肌肉相连的运动神经元以控制的 运动停止工作并最终死亡。但是，初始之间似乎有很大的延迟 神经元功能障碍和身体变性。复杂的神经系统是由于细胞而部分维持的 对压力的弹性以维持功能并抵抗激活细胞死亡过程。实验 提案将研究一个新的假设：ALS中的神经元作为复杂的一部分进入细胞衰老 压力反应以避免主动变性和细胞死亡。但是，尽管这种保护机制可能 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组促进 随着时间的流逝，慢性组织变性促进了疾病进展。衰老被蛋白质激活 在其他神经退行性疾病中积累。在这里，我们将确定TDP43是否沉积 通过评估死后人脑和脊柱的差异影响细胞衰老应激反应 从VA ALS Biorepository脑库访问的资深捐赠者的绳索，任何TDP43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数字空间分析技术。这种高分辨率，高质量的非破坏性分析方法 在保持空间分辨率的同时，可以研究单细胞水平上的100s蛋白质。这 具有将数据映射回组织以将蛋白质表达差异与细胞相关的能力 形态学，组织中的位置，细胞外环境以及靠近血管和 /或其他病理。 我们的研究建议产生的数据将为深入的信息提供了前所未有的严格信息。 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 许多新型的ALS研究途径，并有可能将细胞衰老作为一种新的治疗方法提出 目标。这是一个迫切需要发展的领域，因为大多数ALS患者平均死亡，2-4 诊断后的几年。