The classical complement system in post-traumatic thalamic neuroinflammation

项目总结和摘要 创伤性脑损伤（TBI）每年影响全球6900万人。尽管TBI很普遍， 仍然没有得到充分的治疗，以至于疾病控制和预防中心将其称为 “无声的流行病”。TBI没有可行的治疗方法，但长期后果可能是严重的残疾。 例如，高达50%的TBI患者将发展为慢性创伤后癫痫（PTE），并且大多数患者将 报告睡眠障碍，如睡眠碎片和失眠。 这些创伤后缺陷起源的主要候选者是丘脑炎症。深脑 丘脑结构在TBI后经常显示出强烈的神经胶质增生和炎症的迹象，即使原发性损伤急性 会影响大脑皮层丘脑是睡眠的连接点，它与皮质的紧密相互连接使睡眠更容易发生。 会引起癫痫在Paz实验室的研究表明，异常的补体激活， 丘脑，特别是高水平的补体因子C1q，可导致创伤后 癫痫活动和睡眠纺锤波减少，非REM睡眠的电生理特征被认为 对记忆巩固至关重要现在的问题仍然是C1q如何发挥其适应不良的影响。的 拟议的研究将通过诱导性基因缺失来研究适应不良C1q的细胞来源， EEG和免疫组化，并将确定小胶质细胞的作用，其功能在突触 已知修剪受C1q调节，可能在介导C1q引起的电生理异常中起作用 (Aim 1）。拟议的研究还将探讨经典补体途径的参与程度 通过应用一种针对C4b、C1q的高度新颖的纳米抗体， 直接下游效应器（Aim 2），结合许多EEG和分子技术， 目标1.这些研究的最终目标是确定潜在的治疗途径， 治疗TBI及其导致的缺陷，包括PTE和睡眠中断。 所有的研究将在加州大学旧金山分校和格莱斯顿研究所进行，并将受益于丰富的 这两个机构都有资源和培训。他们将通过内部数据科学和统计学来丰富 工具和课程，并从内部和外部合作中获益。所有的实验都将遵循 指导赞助商Jeanne Paz博士，并提供反馈和演示， 各种会议。

PROJECT SUMMARY AND ABSTRACT Traumatic brain injury (TBI) impacts 69 million individuals worldwide every year. Despite its prevalence, TBI continues to be undertreated, so much so that the Centers for Disease Control and Prevention has dubbed it a “silent epidemic”. TBI boasts no viable treatments, yet the long-term consequences can be profoundly disabling. For example, up to 50% of TBI patients will develop chronic post-traumatic epilepsy (PTE), and a majority will report sleep disturbances like sleep fragmentation and insomnia. A leading candidate for the origin of these post-traumatic deficits is thalamic inflammation. Deep-brain thalamic structures often show signs of robust gliosis and inflammation after TBI, even if the primary injury acutely affects the cortex. The thalamus is a nexus for sleep, and its dense reciprocal connectivity with the cortex render it highly epileptogenic. Studies in the Paz laboratory have shown that aberrant complement activation in the thalamus, and in particular high levels of complement factor C1q, can lead to the development of post-traumatic epileptic activity and a reduction in sleep spindles, electrophysiological signatures of non-REM sleep thought to be crucial for memory consolidation. The question now remains how C1q exerts its maladaptive effects. The proposed research will investigate the cellular source of maladaptive C1q through inducible genetic deletion, EEG, and immunohistochemistry, and will determine the role that microglia—cells whose function in synaptic pruning is known to be modulated by C1q—may play in mediating electrophysiological abnormalities due to C1q (Aim 1). The proposed research will also explore the extent of the classical complement pathway’s participation in the rise of epileptic events and sleep spindle loss by applying a highly novel nanobody against C4b, C1q’s immediate downstream effector (Aim 2), coupled with many of the EEG and molecular techniques described in Aim 1. These studies will be conducted with the ultimate goal of identifying avenues for potential therapeutic treatment for TBI and its resultant deficits, including PTE and sleep disruption. All research will be conducted at UCSF and at Gladstone Institutes and will benefit from the wealth of resources and training available at both institutions. They will be enriched by in-house data science and statistics tools and courses, and profit from internal and external collaborations. All experiments will be guided by the mentorship of supervising sponsor Dr. Jeanne Paz, and made available for feedback and presentation at conferences and meetings.