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

项目概述：神经系统疾病，如癫痫和记忆丧失，发展后几年 创伤性脑损伤是脑创伤后身体残疾和经济负担主要来源。的 初始损伤和疾病之间的时间窗表明，脑损伤后发生的进行性变化， 损伤是神经系统疾病的基础，早期干预可能会防止这些使人衰弱的结果。的 海马齿状回是脑震荡后神经元损伤和兴奋性增加的主要焦点 脑损伤和创伤后颞叶癫痫。除了损伤神经元外， 来自破裂细胞和细胞外基质的内源性分子可以激活模式识别受体 包括Toll样受体。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。这一提议的核心假设是， 损伤后早期神经元TLR4活化的增加改变了兴奋性，并导致神经元的兴奋性毒性损伤。 特定的齿状神经元类型和促进网络兴奋性的急性和慢性增加。使用 啮齿类动物脑震荡液压损伤模型及现代生理学技术，目的1 将区分细胞，信号和通道机制的TLR4调节神经元 正常脑和脑损伤后早期的兴奋性。目的2将确定是否TLR4激活， 特定的中间神经元群导致兴奋性毒性损伤和某些中间神经元亚型的丧失。 最后，目标3将使用组织学、生理学和行为学分析的组合来测试是否 选择性TLR4拮抗剂降低脑损伤后癫痫和记忆缺陷的长期易感性。它 预计拟议的研究将确定扰动TLR4信号转导在创伤后的新作用。 病理学，并制定有针对性的治疗策略，以改善长期神经系统的结果后， 创伤性脑损伤同时保持正常生理状态这种预防性战略将大大改善 脑损伤后患者的生活质量，并与NINDS使命保持一致，减少 创伤后神经系统疾病的医疗保健系统。

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.