A Novel TrkB Agonist To Promote Motor Recovery After TBI

一种促进 TBI 后运动恢复的新型 TrkB 激动剂

基本信息

批准号：
9033155
负责人：
Jeffrey A Kleim
金额：
$ 22.44万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9033155
关键词：
Adjuvant Therapy Affect Aftercare Agonist Animal Model Animals Behavioral Binding Biochemical Blood - brain barrier anatomy Brain Brain Injuries Brain-Derived Neurotrophic Factor Caring Clinical Contralateral Data Development Dose Forelimb Health Healthcare Immunoblotting Impairment Injury Ischemia Learning Lesion Life Maps Mediating Medical Motor Motor Cortex Movement Neuronal Plasticity Neurorehabilitation Neurotrophic Tyrosine Kinase Receptor Type 2 PI3 gene Pathway interactions Patients Phosphorylation Physically Handicapped Proto-Oncogene Proteins c-akt Quality of life Receptor Signaling Recovery Rehabilitation therapy Rodent Model Role Signal Pathway Signal Transduction Signaling Protein Synapses System Testing Training Translating Traumatic Brain Injury Traumatic Brain Injury recovery United States Up-Regulation controlled cortical impact disability efficacy testing experience inhibitor/antagonist kinase inhibitor microstimulation motor deficit motor impairment motor recovery motor rehabilitation neurophysiology neurotransmission novel novel therapeutics pre-clinical prevent receptor receptor binding research study response

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) continues to be a growing health concern in the United States. Motor deficits represent one of the major impairments experienced by TBI patients and most will live with enduring physical disabilities. One of the major challenges of neurorehabilitation is to identify adjuvant therapies that can amplify the impact of motor rehabilitation by harnessing key neural signaling systems known to drive compensatory and restorative neural plasticity. The TrkB receptor has emerged as one of the key signaling systems orchestrating such plasticity. Modulating this system, however, has proven difficult due to a lack of a selective TrkB agonist that can be easily delivered to the brai. A recently discovered compound, LM22A-4, has been shown to selectively activate the TrkB receptor and readily cross the blood brain barrier. The proposed experiments will take advantage of this novel compound to test the hypothesis that LM22A-4 enhances rehabilitation-dependent motor recovery and motor cortex plasticity after TBI. The effect of daily LM22A-4 treatment on forelimb motor function and the topography of forelimb movement representations will be studies using a well established rodent model of TBI. To further determine the role of TrkB receptor signaling in rehabilitation-dependent motor recovery and cortical plasticity, we will chronically disrupt TrkB signaling in both LM22A-4 and vehicle treated animals. Intracortical microstimulation will be used to derive motor maps of the forelimb contralateral to the lesion. Quantitative immunoblotting will be used to confirm changes in TrkB receptor phosphorylation and expression of downstream signaling proteins. We hypothesize that disrupting TrkB signaling will prevent enhanced motor recovery and motor map reorganization in LM22A-4 treated animals. The results have the potential to guide the development of novel therapies to enhance the quality of life in TBI patients.

描述（由适用提供）：在美国，创伤性脑损伤（TBI）仍然是日益严重的健康问题。马达定义了TBI患者所经历的主要影响之一，大多数人将患有持久的身体疾病。神经康复的主要挑战之一是鉴定辅助疗法可以通过利用已知可驱动补偿性和恢复性中性可塑性的关键神经信号系统来扩大运动康复的影响。 TRKB受体已成为策划这种可塑性的关键信号系统之一。然而，由于缺乏选择性的TRKB激动剂，可以轻松地传递到Brai，因此很难调节该系统。最近发现的化合物LM22A-4已被证明可以选择性地激活TRKB受体并容易穿越血脑屏障。提出的实验将利用这种新颖的化合物来检验以下假设：LM22A-4可以增强TBI后康复依赖性运动恢复和运动皮层可塑性。每日LM22A-4处理对前肢运动功能和前肢运动表示形态的影响将使用良好的TBI啮齿动物模型进行研究。为了进一步确定TRKB受体信号在康复依赖性运动恢复和皮质可塑性中的作用，我们将在LM22A-4和媒介物处理的动物中，长期破坏TRKB信号传导。皮质内微刺激将用于导出前肢的运动图与病变对侧。定量免疫印迹将用于确认TRKB受体磷酸化和下游信号蛋白表达的变化。我们假设破坏TRKB信号会阻止LM22A-4治疗动物的运动恢复和运动图的重组。结果有可能指导新疗法的发展，以提高TBI患者的生活质量。