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.

项目总结/文摘