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Role of UCHL1 in Axonal Injury and Recovery after TBI

UCHL1 在 TBI 后轴突损伤和恢复中的作用

基本信息

批准号：
10199060
负责人：
C EDWARD DIXON
金额：
$ 40.47万
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：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199060
关键词：
Acute Address Amyloid beta-Protein Precursor Animal Model Autophagocytosis Axon Axonal Transport Behavior Binding Sites Blood - brain barrier anatomy Brain Capsid Proteins Cell Death Cerebral Ischemia Cerebrum Chimeric Proteins Clinical Trials Cognitive Cognitive deficits Cysteine Cytoskeleton Data Diffuse Axonal Injury Dose Enzymes Excision Goals Half-Life Hippocampus (Brain)Histologic Hydrolase In Vitro Injury Knock-in Mouse Knowledge Laboratories Lipid Binding Lipids Long-Term Potentiation Mechanics Mediating Memory Modeling Molecular Motor Mus Mutation Neurons Outcome Pathway interactions Patients Permeability Play Process Proteins Recovery Recovery of Function Resistance Role Site Stretching TBI treatment Testing Trans-Activators Transcription Coactivator Translating Traumatic Brain Injury Traumatic Brain Injury recovery Ubiquitin Wild Type Mouse axon injury behavioral outcome cognitive function controlled cortical impact design immunocytochemistry improved improved outcome in vivo injury recovery insight motor behavior motor deficit motor function improvement multicatalytic endopeptidase complex neuron loss novel novel strategies preservation prevent repaired restoration safety and feasibility selective expression synaptic function tat Protein treatment strategy ubiquitin C-terminal hydrolase

项目摘要

Diffuse axonal injury is a major component of the motor and cognitive sequela of traumatic brain injury (TBI). Ubiquitin C-terminal hydrolase L1 (UCHL1) is expressed at high concentrations in neurons and may play an important role axonal transport and synaptic function. UCHL1's activity is important in degrading abnormal neuronal protein via the ubiquitin proteasome pathway. Thus, UCHL1 may play an important role in recovery after injury via several mechanisms. In preliminary studies, a TAT-UCHL1 protein was constructed that readily enters the brain when given i.p. Treatment with TAT-UCHL1 reduced axonal injury detected by APP immunocytochemistry and decreased hippocampal cell death after controlled cortical impact (CCI) in mice. A reactive lipid binding site at the 152 cysteine of UCHL1 was identified that is responsible for unfolding and inactivating the enzyme. A knock-in mouse bearing a C152A mutation was constructed and found to have significantly reduced axonal injury and improved motor behavior after CCI. A mouse bearing a C90A mutation with UCHL1 activity that is devoid of hydrolase activity was also constructed. The goals of the current study are: 1) Determine the role of the UCHL1 C152 site in axonal injury, neuronal death, and motor and cognitive behavior after CCI in mice. 2) Determine the role of UCHL1 hydrolase activity in axonal injury, neuronal death, and motor and cognitive behavior after CCI in mice. 3) Test whether systemic treatment with TAT-UCHL1 fusion proteins will reduce axonal injury in the in vitro stretch model and in vivo TBI model, and improve long term motor and cognitive function after CCI in mice. The broad long term objective of these studies is to develop novel approaches that promote axonal preservation and functional recovery after TBI. Completion of these studies will improve scientific knowledge regarding the role of UCHL1 in neuronal repair and functional recovery after TBI and test novel TAT-UCHL1 proteins as a novel strategy to address axonal injury.

弥漫性轴索损伤是运动和认知后遗症的主要组成部分，创伤性脑损伤（TBI）。泛素C-末端水解酶L1（UCHL 1）以高水平表达，在神经元中的浓度，并可能发挥重要作用的轴突运输和突触功能UCHL 1的活性在通过泛素降解异常神经元蛋白中是重要的蛋白酶体途径因此，UCHL 1可能通过以下途径在损伤后的恢复中发挥重要作用：几种机制。在初步研究中，构建了TAT-UCHL 1蛋白，用TAT-UCHL 1治疗减少了通过以下检测到的轴突损伤： APP免疫细胞化学和减少海马细胞死亡后，控制皮质影响（CCI）。在UCHL 1的152个半胱氨酸处发现了一个反应性脂质结合位点它负责展开和灭活酶。一只带有构建了C152 A突变，发现其显著减少了轴突损伤，改善CCI后的运动行为。携带具有UCHL 1活性的C90 A突变的小鼠，也构建了缺乏水解酶活性的。本研究的目的是：1）确定UCHL 1 C152位点在 CCI后小鼠的轴突损伤、神经元死亡以及运动和认知行为。（二）确定UCHL 1水解酶活性在轴突损伤、神经元死亡和神经元损伤中的作用。 CCI后小鼠的运动和认知行为。3)测试是否使用 TAT-UCHL 1融合蛋白将减少体外牵张模型中的轴突损伤，体内TBI模型，并改善CCI后小鼠的长期运动和认知功能。这些研究的广泛的长期目标是开发新的方法，促进TBI后轴突保存和功能恢复。完成这些研究将提高关于UCHL 1在神经元修复和功能中作用的科学知识 TBI后的恢复和测试新的TAT-UCHL 1蛋白作为解决轴突损伤的新策略损伤