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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：
9156763
负责人：
Vijayalakshmi Santhakumar
金额：
$ 34.55万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
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：几年后出现的神经系统疾病，例如癫痫和记忆丧失外伤性脑损伤是脑外伤后造成身体残疾和经济负担的主要原因。这最初的损伤和疾病之间的时间窗口表明，大脑在损伤是神经系统疾病的基础，早期干预可能会预防这些使人衰弱的后果。这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，创伤性释放来自破碎细胞和细胞外基质的内源性分子可以激活模式识别受体先天免疫系统，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。该提案的中心假设是，损伤后早期神经元 TLR4 激活的增加改变了兴奋性并导致神经元兴奋性毒性损伤特定的齿状神经元类型并促进网络兴奋性的急性和慢性增加。使用啮齿动物脑震荡液体冲击损伤模型和当前生理技术，目标 1 将区分 TLR4 调节神经元的细胞、信号传导和通道机制正常大脑和脑损伤后早期的兴奋性。目标 2 将确定 TLR4 是否激活特定的中间神经元群体会导致兴奋性毒性损伤和某些中间神经元亚型的丧失。最后，Aim 3 将结合组织学、生理学和行为分析来测试是否选择性 TLR4 拮抗剂可降低脑损伤后对癫痫和记忆缺陷的长期易感性。它预计拟议的研究将确定受干扰的 TLR4 信号传导在创伤后恢复中的新作用病理学并制定针对性治疗策略，以改善术后长期神经学结果创伤性脑损伤，同时保持正常生理机能。这种预防策略将大大改善脑损伤后患者的生活质量，并根据 NINDS 的使命，减轻患者的负担创伤后神经系统疾病影响医疗保健系统。