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

项目概述：癫痫和记忆力丧失等神经性疾病在几年后发展 创伤性脑损伤是脑外伤后身体残疾和经济负担的主要来源。这个 最初的侮辱和疾病之间的时间窗口表明，大脑之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衰弱的结果。这个 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，创伤性释放 破坏的细胞和细胞外基质中的内源性分子可以激活模式识别受体 包括Toll样受体在内的先天免疫系统。某些TLR亚型，包括TLR4是 在神经元中表达，调节神经发生和细胞死亡。这一提议的中心假设是， 损伤后早期神经元TLR4活性增加改变兴奋性并导致兴奋性损伤 特定的齿状神经元类型，促进网络兴奋性的急性和慢性增加。使用 脑震荡伤啮齿动物流体冲击伤模型及生理学研究进展 将区分神经元TLR4调制的细胞、信号和通道机制 正常大脑和脑损伤后早期的兴奋性。AIM 2将确定TLR4是否在 特定的神经元间群导致兴奋性毒性损伤和某些神经元间亚型的丧失。 最后，目标3将使用组织学、生理和行为分析的组合来测试 选择性的TLR4拮抗剂可降低脑损伤后癫痫和记忆障碍的长期易感性。它 预计拟议的研究将确定受扰的TLR4信号在创伤后的新角色 病理学和制定靶向治疗的策略，以改善术后长期神经预后 创伤性脑损伤，同时保留正常的生理。这种预防策略将极大地改善 提高脑损伤后患者的生活质量，并根据NINDS的使命，减少 创伤后神经系统疾病对医疗保健系统造成了不利影响。

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.