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Investigating calcineurin regulation of pathological TDP-43 phosphorylation in ALS

研究钙调神经磷酸酶对 ALS 病理性 TDP-43 磷酸化的调节

基本信息

批准号：
10292956
负责人：
Nicole Faron Liachko
金额：
--
依托单位：
VA PUGET SOUND HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-10-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10292956
关键词：
Affect American Americas Amyotrophic Lateral Sclerosis Binding Brain Caenorhabditis elegans Calcineurin Calmodulin Cell Culture Techniques Cessation of life Code Data Degenerative Disorder Diagnostic Disease Disease Progression Event FDA approved Genes Genetic Health Innate Immune Response Institutes Lead Life Mammalian Cell Medicine Military Personnel Modeling Molecular Motor Neurons Muscular Atrophy Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurologic Neuronal Dysfunction Neurons Paralysed Pathologic Pathology Pathway interactions Peptide aptamers Pharmaceutical Preparations Phosphorylation Post-Translational Protein Processing Process Protein Dephosphorylation Proteins RNA Interference Recovery Regulation Risk Role Serine Services Signal Transduction Spinal Cord Stress Testing Therapeutic Intervention United States Department of Veterans Affairs United States National Academy of Sciences Validation Vertebrates Veterans Work amyotrophic lateral sclerosis therapy calcineurin phosphatase design disability disease phenotype effective therapy experimental study gain of function mutation genome editing genomic tools illness length motor neuron degeneration mutant neurotoxic neurotoxicity new therapeutic target novel novel therapeutic intervention pre-clinical premature protein TDP-43 response targeted treatment therapeutic development therapeutic target translational approach

项目摘要

Amyotrophic lateral sclerosis (ALS) is a severe progressive neurodegenerative disease characterized by degeneration of motor neurons in the brain and spinal cord, resulting in neurogenic muscle wasting, paralysis, and death. Nearly 95% of ALS cases have pathology featuring phosphorylated inclusions of the TDP-43 protein in neurons and glial cells. Furthermore, mutations in the gene coding for TDP-43 have been shown to cause some cases of ALS, indicating normal TDP-43 is critical for neuronal health. Phosphorylation of TDP-43 reduces its turnover, increases its aggregation, and promotes neurotoxicity and neurodegeneration. Recent work has identified the phosphatase calcineurin as a key regulator of phosphorylated TDP-43 (pTDP) accumulation. By dephosphorylating pTDP, calcineurin reduces levels of neurotoxic pTDP and protects against disease phenotypes, including neurodegeneration. An understanding of the mechanisms controlling TDP-43 pathology in ALS is critical to the design of neuroprotective strategies. This proposal describes experiments exploring the cellular and molecular changes that promote TDP-43-targeted calcineurin phosphatase activity, with a focus on the development of therapeutic interventions for the treatment of ALS. This work will 1) elucidate mechanisms controlling calcineurin activation and pTDP clearance, 2) evaluate activation of calcineurin as a novel therapeutic strategy for the clearance of pTDP, 3), provide new information about cellular recovery following neurotoxic stress, and 4) may provide additional targets for therapeutic intervention. Completion of this work will advance understanding of the disease processes underlying ALS and provide preclinical validation of a new therapeutic approach.

肌萎缩侧索硬化症是一种严重的进行性神经退行性疾病以脑和脊髓中的运动神经元变性为特征，导致神经原性肌肉消瘦瘫痪和死亡近95%的ALS病例的病理特征是磷酸化神经元和神经胶质细胞中TDP-43蛋白的内含物。此外，基因编码的突变 TDP-43已被证明会导致一些ALS病例，表明正常的TDP-43对神经元的生长至关重要。健康TDP-43的磷酸化降低了其周转，增加了其聚集，并促进了细胞增殖。神经毒性和神经变性。最近的工作已经确定磷酸酶钙调神经磷酸酶作为一个关键磷酸化TDP-43（pTDP）积累的调节剂。通过去磷酸化pTDP，钙调磷酸酶降低神经毒性pTDP的水平，并防止疾病表型，包括神经变性。理解ALS中控制TDP-43病理学的机制对于设计治疗方案至关重要。神经保护策略该提案描述了探索细胞和分子变化的实验， TDP-43靶向的钙调磷酸酶活性，重点是开发治疗治疗ALS的干预措施。本工作将1）阐明钙调神经磷酸酶的调控机制激活和pTDP清除，2）评估钙调磷酸酶的激活作为一种新的治疗策略， pTDP的清除，3）提供了关于神经毒性应激后细胞恢复的新信息，和4）可以为治疗干预提供额外的靶点。这项工作的完成将促进了解ALS潜在的疾病过程，并提供一种新的治疗方法