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.

弥漫性轴突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 (UCHL1) 高表达神经元中的浓度，可能在轴突运输和突触中发挥重要作用功能。 UCHL1 的活性对于通过泛素降解异常神经元蛋白非常重要蛋白酶体途径。因此，UCHL1可能通过以下方式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-UCHL1 蛋白，该蛋白很容易腹腔注射时进入大脑TAT-UCHL1 治疗减少了轴突损伤 APP 免疫细胞化学和控制皮质后海马细胞死亡减少对小鼠的影响（CCI）。鉴定出 UCHL1 152 半胱氨酸处的反应性脂质结合位点它负责展开和灭活酶。带有一个基因敲入小鼠构建了 C152A 突变，发现显着减少了轴突损伤，并且 CCI 后运动行为得到改善。携带具有 UCHL1 活性的 C90A 突变的小鼠还构建了缺乏水解酶活性的。当前研究的目标是： 1) 确定 UCHL1 C152 位点在小鼠 CCI 后的轴突损伤、神经元死亡以及运动和认知行为。 2）确定 UCHL1 水解酶活性在轴突损伤、神经元死亡和神经元死亡中的作用小鼠 CCI 后的运动和认知行为。 3) 测试是否进行全身治疗 TAT-UCHL1 融合蛋白将减少体外拉伸模型和体内 TBI 模型，并改善小鼠 CCI 后的长期运动和认知功能。这些研究的广泛长期目标是开发新方法促进 TBI 后轴突的保存和功能恢复。完成这些研究将提高有关 UCHL1 在神经元修复和功能中作用的科学知识 TBI 后恢复并测试新型 TAT-UCHL1 蛋白作为解决轴突的新策略受伤。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mutation of a Ubiquitin Carboxy Terminal Hydrolase L1 Lipid Binding Site Alleviates Cell Death, Axonal Injury, and Behavioral Deficits After Traumatic Brain Injury in Mice.

泛素羧基末端水解酶 L1 脂质结合位点的突变可减轻小鼠脑外伤后的细胞死亡、轴突损伤和行为缺陷。

DOI：
发表时间：
2021-11-01
期刊：
影响因子：
3.3
作者：
Mi, Zhiping;Liu, Hao;Rose, Marie E;Ma, Jie;Reay, Daniel P;Ma, Xiecheng;Henchir, Jeremy J;Dixon, C Edward;Graham, Steven H
通讯作者：
Graham, Steven H