Contribution of innate immune receptors to neurological dysfunction after traumatic brain injury: Mechanisms and therapeutic implications

先天免疫受体对创伤性脑损伤后神经功能障碍的作用：机制和治疗意义

基本信息

批准号：
9901603
负责人：
Vijayalakshmi Santhakumar
金额：
$ 30.99万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-03-31
项目状态：
已结题

项目摘要

Project Summary: Neurological disorders such as epilepsy and memory loss that develop several years after traumatic brain injury are a major source of physical disability and economic burden after brain trauma. The time window between the initial insult and the disease suggest that progressive changes that occur after brain injury underlie neurological disease and that early interventions might prevent these debilitating outcomes. The hippocampal dentate gyrus is the major focus of neuronal damage and increased excitability after concussive brain injury and in post-traumatic temporal lobe epilepsy. Apart from injuring neurons, traumatic release of endogenous molecules from disrupted cells and extracellular matrix can activate pattern-recognition receptors of the innate immune system including Toll-like receptors. Certain TLR subtypes, including TLR4 are expressed in neurons and regulate neurogenesis and cell death. The central hypothesis of this proposal is that, early post-injury increase in activation of neuronal TLR4 alters excitability and leads to excitotoxic damage of specific dentate neuronal types and facilitating acute and chronic increases in network excitability. Using the rodent fluid percussion injury model of concussive brain trauma and current physiological techniques, Aim 1 will distinguish the cellular, signaling and channel mechanisms underlying TLR4 modulation of neuronal excitability in the normal brain and early after brain injury. Aim 2 will determine whether TLR4 activation in specific interneuronal populations contributes to excitotoxic injury and loss of certain interneuronal subtypes. Finally, Aim 3 will use a combination of histological, physiological and behavioral assays to test whether selective TLR4 antagonists reduce long-term susceptibility to epilepsy and memory deficits after brain injury. It is anticipated that the proposed studies will identify novel roles for perturbed TLR4 signaling in post-traumatic pathology and generate strategies for targeted treatment to improve the long-term neurological outcome after traumatic brain injury while preserving normal physiology. Such preventive strategies will greatly improve the quality of life of patients after brain injury and, in keeping with the NINDS mission, decrease the burden that post-traumatic neurological diseases place on the health care system.

项目摘要：几年后发展的神经系统疾病，例如癫痫和记忆力下降创伤性脑损伤是脑创伤后身体残疾和经济负担的主要来源。这初始侮辱和疾病之间的时间窗口表明大脑后发生的渐进变化损伤是神经系统疾病和早期干预措施的基础，可能会阻止这些令人衰弱的结果。这海马齿状回是神经元损伤的主要重点，脑震荡后增加了兴奋性脑损伤和创伤后颞叶癫痫。除了受伤的神经元外，来自破坏细胞和细胞外基质的内源分子可以激活模式识别受体先天免疫系统，包括收费受体。某些TLR亚型，包括TLR4 在神经元中表达并调节神经发生和细胞死亡。该提议的核心假设是，神经元TLR4激活的早期伤害增加，改变了兴奋性，并导致兴奋性损害的损害特定的齿状神经元类型以及促进网络兴奋性的急性和慢性增加。使用脑震荡脑创伤和当前生理技术的啮齿动物液体打击乐损伤模型，目标1 将区分神经元调节的细胞，信号传导和通道机制正常大脑和脑损伤后早期的兴奋性。 AIM 2将确定TLR4是否激活特定的神经元种群导致兴奋性毒性损伤和某些神经元亚型的丧失。最后，AIM 3将使用组织学，生理和行为测定的组合来测试是否是否选择性TLR4拮抗剂可减少脑损伤后对癫痫和记忆缺陷的长期敏感性。它预计拟议的研究将确定创伤后扰动TLR4信号传导的新作用病理学并生成针对性治疗的策略，以改善长期神经系统结局脑损伤的同时保留正常的生理。这种预防策略将大大改善脑损伤后患者的生活质量，并与NINDS任务保持一致，减轻了负担创伤后神经疾病在医疗保健系统上。