Trk Ligands for Treatment of Traumatic Brain Injury

用于治疗创伤性脑损伤的 Trk 配体

• 批准号: 9280751
• 负责人: STEPHEN M. MASSA
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280751
• 关键词: Acute; Address; Adult; Anxiety; Apoptotic; Behavior; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; Cause of Death; Cell Death; Cell Differentiation process; Cell Proliferation; Cell Survival; Cells; Chemicals; Chronic; Clinical; Coupled; Craniocerebral Trauma; Dendritic Spines; Development; Dose; Down-Regulation; Drug Kinetics; Early treatment; Effectiveness; Exhibits; Explosion; General Population; Generations; Goals; Growth; Hippocampus (Brain); In Vitro; Inflammation; Inflammatory Response; Injury; Knowledge; Ligands; MAPK3 gene; MAPK7 gene; Mediating; Memory; Mental Depression; MicroRNAs; Modeling; Modernization; Morphology; NGFR Protein; Natural regeneration; Nature; Nerve Cell Survival; Nerve Growth Factor Receptors; Neurites; Neurologic; Neuronal Differentiation; Neuronal Plasticity; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 3; Oral Administration; PI3K/AKT; Pain; Pathologic; Pathway interactions; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phosphotransferases; Population; Process; Proliferating; Property; Protein Tyrosine Kinase; Proteins; Rattus; Recovery; Research; Role; Signal Pathway; Signal Transduction; Specificity; Testing; Therapeutic; Tissues; Traumatic Brain Injury; Traumatic CNS injury; Tropomyosin; Vertebral column; Veterans; Viral; Work; base; behavioral outcome; central nervous system injury; combat; controlled cortical impact; disability; dosage; experimental study; falls; field study; gait examination; gliogenesis; improved; in vivo; inhibitor/antagonist; insight; morris water maze; motor learning; mutant; nerve stem cell; neuroblast; neurogenesis; neuron loss; neuronal survival; neurotrophic factor; neurotropin; novel therapeutics; polypeptide; progenitor; public health relevance; receptor; repaired; response; small molecule; subventricular zone; symptomatic improvement; vehicular accident

DESCRIPTION (provided by applicant): Traumatic brain injuries (TBIs) constitute a significant and growing percentage of injuries in the veteran population; sequelae of explosions, motor vehicle accidents and falls. TBI is also a major cause of death and disability in the general population of the US, particularly in those under 40. Approximately 2% of the population is living with a chronic TBI-related disability. There are currently no effective protective or restorative therapies available clinically. In severl models of CNS trauma, administration of a neurotrophin (e.g. BDNF, NGF) protects tissues acutely and promotes longer term recovery. However, the neurotrophins are poor drugs as they are labile, exhibit poor CNS penetration and may augment cell death and pain pathways. These properties are due to their polypeptide composition and the stimulation of intersecting signalling pathways through the activation of multiple receptors. These problems may be at least partially circumvented through the use of recently discovered small, stable, non-peptidyl drug-like compounds (designated LM22) that promote neuronal survival through selective interactions with the Trk neurotrophin receptors (LM22A-4 with TrkB and LM22B-10 with TrkB and TrkC). The compounds inhibit neuronal death, promote neural progenitor cell proliferation and differentiation and augment functional and morphologic neuroplasticity. We hypothesize that the LM22 compounds will: increase neural progenitor survival and differentiation through distinct mechanisms involving activation of specific Trk-coupled survival and differentiative signalling pathways; that increasing TrkB signaling following TBI will promote early neuronal and neural progenitor survival and longer term plasticity, with effects on neuronal processes and spines; that activation of TrkB and TrkC together will be more effective than either alone, and; that while the compounds should improve behavioral outcomes, prolonged or excessive increased plasticity may be detrimental. Specific Aims are to: 1. Determine LM22 compound effects on hippocampal progenitors in vitro: A) Examine the effects of LM22A-4 and LM22B-10 on proliferation, survival, neuro- and/or gliogenic differentiation and morphology of hippocampal neural progenitor cells in vitro, in comparison with neurotrophin protein ligands; B) determine the Trk specificity of the compounds for these effects using selectively inhibitable tyrosine kinase mutants of TrkB, TrkC or both receptors and; C) determine the role of PI3K/AKT, ERKs 1, 2 and 5, PLC�, miRNA9 and NRSF/REST in compound effects, using selective chemical inhibitors, miRNA-mediated downregulation and viral construct-mediated enforced expression; 2. Determine LM22 compound effects on cellular responses relative to dose and timing of administration in the rat controlled cortical impact (CCI) model of TBI: assess A) neuronal and neural progenitor cell death; B) Trk activation and downstream signaling; C) neuro/gliogenesis and neuronal morphology and; D) inflammation, and; 3. Determine LM22 compound effects on behavior following rat CCI: Examine A): spatial/hippocampal memory (Morris Water Maze); B) anxiety/depression (open field testing, elevated plus maze) and; C) motor learning (rotorod/gait analysis) These studies will provide information important for the eventual application of these or related compounds to clinical head trauma, and will advance our knowledge of the roles of TrkB and TrkC in pathologic states. The overall goal of this research is to advance the application of these neurotrophic compounds to the treatment of brain trauma and other conditions.

描述（由申请人提供）： 创伤性脑损伤（TBI）在退伍军人人群中构成了显著且不断增长的伤害比例;爆炸、机动车事故和福尔斯的后遗症。TBI也是美国普通人群死亡和残疾的主要原因，特别是40岁以下的人群。大约2%的人口患有与TBI相关的慢性残疾。目前临床上没有有效的保护性或恢复性治疗。在CNS创伤的几种模型中，神经营养因子（例如BDNF、NGF）的施用急性保护组织并促进长期恢复。然而，神经营养因子是差的药物，因为它们不稳定，表现出差的CNS渗透，并且可能增加细胞死亡和疼痛途径。这些特性是由于它们的多肽组成和通过激活多种受体刺激交叉信号通路。这些问题可以通过使用最近发现的小的、稳定的、非肽基药物样化合物（命名为LM 22）至少部分地避免，所述化合物通过与Trk神经营养因子受体（LM 22 A-4与TrkB和LM 22 B-10与TrkB和TrkC）的选择性相互作用促进神经元存活。所述化合物抑制神经元死亡，促进神经祖细胞增殖和分化，并增强功能和形态神经可塑性。通过涉及特异性Trk偶联的存活和分化信号传导途径的活化的不同机制增加神经祖细胞存活和分化; TBI后增加TrkB信号传导将促进早期神经元和神经祖细胞存活和长期可塑性，对神经元过程和棘有影响; TrkB和TrkC一起激活比单独激活更有效， 所述化合物应改善行为结果，但延长或过度增加的可塑性可能是有害的。具体目标是：1。测定LM 22化合物对体外海马祖细胞的作用：A）与神经营养蛋白配体相比，检查LM 22 A-4和LM 22 B-10对体外海马神经祖细胞的增殖、存活、神经元和/或胶质细胞分化和形态的作用; B）测定LM 22 A-4和LM 22 B-10对体外海马神经祖细胞的增殖、存活、神经元和/或胶质细胞分化和形态的作用。 使用TrkB、TrkC或两种受体的选择性可重复的酪氨酸激酶突变体，化合物对这些效应的Trk特异性; C）使用选择性化学抑制剂、miRNA介导的下调和病毒构建体介导的强制表达，确定PI 3 K/AKT、ERK 1、2和5、PLC β、miRNA 9和NRSF/REST在化合物效应中的作用; 2.在TBI的大鼠受控皮质撞击（CCI）模型中，相对于给药的剂量和时间，确定LM 22化合物对细胞应答的影响：评估A）神经元和神经祖细胞死亡; B）Trk活化和下游信号传导; C）神经元/神经胶质发生和神经元形态; D）炎症;和; 3.测定LM 22化合物对大鼠CCI后行为的影响：检查A）：空间/海马记忆（莫里斯水迷宫）; B）焦虑/抑郁（旷场测试，高架加迷宫）和; C.运动学习（旋转杆/步态分析）这些研究将为这些或相关化合物最终应用于临床头部创伤提供重要信息，并将推进我们对TrkB和TrkC在病理状态中的作用的认识。这项研究的总体目标是推进这些神经营养化合物在治疗脑创伤和其他疾病中的应用。