Investigating the role of traumatic injury in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD)

研究创伤性损伤在肌萎缩侧索硬化症和额颞叶痴呆 (ALS/FTD) 中的作用

• 批准号: 10704081
• 负责人: Eric Nathaniel Anderson
• 金额: $ 12.86万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704081
• 关键词: Accounting; Address; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyotrophic Lateral Sclerosis; Animal Model; Autopsy; Behavioral; Biochemical; Biological Models; Brain; Brain Injuries; C9ORF72; Clinical; Cytoplasm; Cytoplasmic Inclusion; Data; Defect; Dementia; Disease; Drosophila genus; Drosophila inturned protein; Exposure to; Fractionation; Frontotemporal Dementia; Functional disorder; Gene Expression; Genes; Genetic; Goals; Human; Immunofluorescence Immunologic; Impairment; Incidence; Injury; Intervention; Lead; Learning; Link; MAPT gene; Manufactured football; Mediating; Memory; Mentors; Modeling; Modification; Molecular; Motor; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurologic Symptoms; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Nucleocytoplasmic Transport Proteins; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phase; Post-Translational Protein Processing; Post-Traumatic Encephalopathy; Pre-Clinical Model; Predisposing Factor; Proteins; Proteomics; Publishing; RNA; RNA-Binding Proteins; Rattus; Regulation; Regulatory Pathway; Research Proposals; Risk; Rodent; Role; Soccer; Spinal Cord; Symptoms; TBI Patients; Tissues; Tobacco; Toxic effect; Toxin; Transcript; Trauma; Traumatic Brain Injury; Traumatic injury; Ubiquitin; Up-Regulation; Validation; Veterans; War; brain tissue; chronic traumatic encephalopathy; clinical epidemiology; cognitive function; combat veteran; differential expression; efficacy evaluation; epidemiology study; experience; familial amyotrophic lateral sclerosis; fly; frontotemporal lobar dementia amyotrophic lateral sclerosis; in vitro Assay; induced pluripotent stem cell; insight; nervous system disorder; neuron loss; neuropathology; novel therapeutic intervention; nucleocytoplasmic transport; protein TDP-43; response; stress granule; tau Proteins; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) and related dementias are devastating human neurodegenerative diseases that share overlapping clinical and pathological features. The majority of ALS/FTD (90-95%) cases are sporadic, and only a small subset (5-10%) of cases are familial. Several extrinsic factors are linked with ALS/FTD and related, including exposure to toxins like BMAA, lead, tobacco, and traumatic brain injury (TBI). Epidemiological studies suggest significantly higher ALS/FTD and related dementia incidences among football players, boxers, soccer players, and war veterans that experience repeated TBI. However, the molecular mechanisms and the contribution of TBI in ALS/FTD pathogenesis are still unknown. About 45% of FTD cases, 95% of ALS cases, and 85 % TBI patients show TDP-43 pathology, while 100% Alzheimer’s disease (AD) and 80% TBI cases have Tau pathology. In fact, TDP-43 positive cytoplasmic inclusions have been shown to predict a decline in cognitive functions suggesting that TDP-43 protein is a pathological marker for a majority of ALS/FTD. We developed and published a TBI fly model to address brain injury and ALS/FTD's clinical association. The TBI model showed pathology (TDP-43, stress granules (SGs), p62, and ubiquitin) and symptoms (motor and learn/memory defects) that are hallmarks of neurodegenerative diseases. Proteomics analysis identified alteration in several unique pathways in response to traumatic injury, such as the nuclear pore complex (NPC), which regulates nucleocytoplasmic transport (NCT). We validated a subset of these proteins in Drosophila, rodent, and CTE postmortem brain tissues. NCT protein validations include nucleoporins. Pathological mutations are known to cause NCT dysfunction in ALS/FTD, but it is unknown how TBI leads to NCT defects and its contribution to pathologies and symptoms in traumatic injury conditions. This proposal seeks to combine Drosophila, rodent, iPSCs and postmortem tissue to accomplish 3 main goals: 1. Aim 1 (Mentored Phase): Determine the mechanism by which TBI mediates NPC protein alteration and nucleocytoplasmic transport defects 2. Aim 2 (Independent Phase): Define the role of NPC protein O-GlcNAcylation in the regulation of TDP-43 pathology and toxicity 3. Aim 3 (Independent Phase): Delineate the transcriptomic landscape changes in the nucleocytoplasmic compartment in traumatic injury. These proposed studies will precipitate insight into the pathophysiologic mechanisms linking TBI and the most prevalent pathologies in ALS/FTD.

项目概要 肌萎缩侧索硬化症和额颞叶痴呆 (ALS/FTD) 及相关痴呆症具有毁灭性 人类神经退行性疾病具有重叠的临床和病理特征。大部分 ALS/FTD (90-95%) 病例是散发性的，只有一小部分 (5-10%) 病例是家族性的。几个外在的 因素与 ALS/FTD 相关，包括接触 BMAA、铅、烟草等毒素 创伤性脑损伤（TBI）。流行病学研究表明 ALS/FTD 和相关的显着升高 经历过的足球运动员、拳击手、足球运动员和退伍军人的痴呆症发病率 重复 TBI。然而，TBI 在 ALS/FTD 发病机制中的分子机制和贡献尚不清楚。 仍然未知。约 45% 的 FTD 病例、95% 的 ALS 病例和 85% 的 TBI 患者表现出 TDP-43 病理学， 而 100% 的阿尔茨海默病 (AD) 和 80% 的 TBI 病例都有 Tau 病理学。事实上，TDP-43呈阳性 细胞质内含物已被证明可以预测认知功能的下降，表明 TDP-43 蛋白质是大多数 ALS/FTD 的病理标志物。 我们开发并发布了 TBI 果蝇模型来解决脑损伤和 ALS/FTD 的临床关联问题。这 TBI 模型显示病理学（TDP-43、应激颗粒 (SG)、p62 和泛素）和症状（运动和症状） 学习/记忆缺陷）是神经退行性疾病的标志。蛋白质组学分析确定 响应创伤性损伤的几种独特途径的改变，例如核孔复合体（NPC）， 它调节核细胞质运输（NCT）。我们在果蝇中验证了这些蛋白质的一个子集， 啮齿动物和 CTE 死后脑组织。 NCT 蛋白质验证包括核孔蛋白。病理性的 已知突变会导致 ALS/FTD 的 NCT 功能障碍，但尚不清楚 TBI 如何导致 NCT 缺陷 及其对创伤性损伤条件下的病理和症状的贡献。该提案旨在 结合果蝇、啮齿动物、iPSC 和死后组织来实现 3 个主要目标： 1. 目标 1（指导阶段）：确定 TBI 介导 NPC 蛋白改变的机制和 核质运输缺陷 2. 目标 2（独立阶段）：明确 NPC 蛋白 O-GlcNAcNA 酰化在 TDP-43 调节中的作用 病理学和毒性 3. 目标 3（独立阶段）：描绘核细胞质中的转录组景观变化 外伤中的隔室。 这些拟议的研究将有助于深入了解 TBI 与大多数疾病之间的联系的病理生理机制。 ALS/FTD 中的常见病理。