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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目摘要肌萎缩性侧索硬化和额颞痴呆（ALS/FTD）和相关痴呆症是毁灭性的具有重叠临床和病理特征的人类神经退行性疾病。大多数 ALS/FTD（90-95％）病例是零星的，只有一小部分（5-10％）是家庭。几个外部因素与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及其相关的更高足球运动员，拳击手，足球运动员和经验丰富的退伍军人的痴呆症发动机重复的TBI。但是，TBI在ALS/FTD发病机理中的分子机制和贡献是仍然未知。大约45％的FTD病例，95％的ALS病例和85％的TBI患者显示TDP-43病理学，而100％阿尔茨海默氏病（AD）和80％TBI病例患有TAU病理学。实际上，TDP-43阳性胞质夹杂物已被证明可以预测认知功能的下降，这表明TDP-43 蛋白质是大多数ALS/FTD的病理标记。我们开发了一个TBI Fly模型，以解决脑损伤和ALS/FTD的临床协会。这 TBI模型显示了病理学（TDP-43，应力颗粒（SG），p62和泛素）和符号（运动和符号学习/记忆缺陷）是神经退行性疾病的标志。确定的蛋白质组学分析响应创伤性损伤的几种独特途径的改变，例如核孔复合物（NPC），调节核细胞质转运（NCT）。我们验证了果蝇中这些蛋白质的子集，啮齿动物和CTE验尸脑组织。 NCT蛋白验证包括核孢子。病理已知突变在ALS/FTD中引起NCT功能障碍，但未知TBI如何导致NCT缺陷及其对创伤性损伤状况中病理和症状的贡献。该提议试图将果蝇，啮齿动物，IPSC和验尸组织结合在一起，以实现3个主要目标： 1。目标1（指导阶段）：确定TBI介导NPC蛋白改变和的机制核质运输缺陷 2。目标2（独立阶段）：定义NPC蛋白O-Glcnacylation在TDP-43调节中的作用病理和毒性 3。目标3（独立阶段）：描述核质核中的转录组景观变化创伤性损伤的腔室。这些拟议的研究将宝贵地深入了解与TBI联系的病理生理机制 ALS/FTD中的普遍病理。