Role of Peripheral Inflammation in TBI Pathobiology

摘要 炎症与大多数脑部疾病有关，被认为是导致疾病病理的因素。 无节制的炎症可导致创伤后的继发性脑损伤和神经变性 脑损伤(TBI)。虽然大多数的脑损伤研究都集中在中枢炎症在脑损伤中的作用 在病理生理学方面，外周炎症的作用还在调查中。一种有害的角色 外周炎症最先是由海伦·布拉姆莱特和他的同事证明的，他们报告说 经腹膜腔注射促炎细胞因子可导致较差的预后。上一首 研究表明，迷走神经刺激可以减少外周炎症和死亡率。 细菌脂多糖(LPS)注射，广泛用于研究炎症、脓毒症和器官衰竭的模型。 随后的研究表明，迷走神经传出的乙酰胆碱能刺激α7烟碱 炎性细胞上的乙酰胆碱受体(α7nAChR)，导致促炎因子释放减少 细胞因子进入血液循环。由于乙酰胆碱在释放后迅速降解，α7nAChR经历快速 脱敏，其他机制可能参与调节外周炎症。我们检查了 迷走神经传出及其胞体定位于迷走神经背侧运动核(DMN) 神经肽，通常与神经递质共同释放，具有相对较长的半衰期。我们 已发现可卡因和苯丙胺调节转录(CARTP)肽(CARTp)高表达 在DMN神经元中的水平。我们建议检验CARTp调节外周血细胞的假设 炎症，可用于改善颅脑损伤的预后。我们将首先通过检查角色来检验这一假设 使用中和CARTp抗体和给药治疗脑损伤相关炎症的迷走神经CARTp 外源性CARTp靶向于脾。使用CRISPR-Cas，我们将删除DMN中的Cartpt基因，并 将测量脑外伤后循环促炎细胞因子的水平。然后我们将测试治疗方法 从CARTP对炎症、血脑屏障(BBB)的影响看其治疗脑外伤的潜力 通透性和炎性细胞渗入受损的脑组织。最后，我们将检查后TBI CARTp 给药可以减少神经元丢失，改善认知结果。性作为一个生物变量将是 评估过了。这些研究的结果将不仅对TBI产生影响，也将对许多 炎症是致病因素的其他疾病。

Abstract Inflammation is associated with most brain diseases and is thought to contribute to disease pathology. Unregulated inflammation can contribute to secondary brain damage and neurodegeneration following traumatic brain injury (TBI). While the majority of TBI research has focused on the role of central inflammation in TBI pathophysiology, the contribution of peripheral inflammation is under investigated. A detrimental role for peripheral inflammation was first demonstrated by Helen Bramlett and colleagues, who reported that intraperitoneal administration of pro-inflammatory cytokines to TBI animals can result in poor outcome. Previous studies have shown that vagus nerve stimulation can reduce both peripheral inflammation and mortality following bacterial lipopolysaccharide (LPS) injection, a widely used model to study inflammation, sepsis and organ failure. Subsequent studies have shown that release of acetylcholine from vagus efferents stimulates α7 nicotinic acetylcholine receptors (α7nAChR) on inflammatory cells, leading to reduced release of pro-inflammatory cytokines into the circulation. As acetylcholine is rapidly degraded after release, and α7nAChR undergo rapid desensitization, additional mechanisms may be involved in regulating peripheral inflammation. We examined the vagus efferents and their cell bodies located in the dorsal motor nucleus of vagus (DMN) for the expression of neuropeptides, which are often co-released with neurotransmitters and have a relatively longer half-lives. We have found that cocaine- and amphetamine-regulated transcript (CART) peptide (CARTp) is expressed at high levels in DMN neurons. We propose to test the hypothesis that that CARTp acts to regulate peripheral inflammation and can be used to improve TBI outcome. We will first test this hypothesis by examining the role of vagus CARTp in TBI-associated inflammation using neutralizing CARTp antibodies and administration of exogenous CARTp targeted to the spleen. Using CRISPR-Cas, we will delete the Cartpt gene in the DMN, and will measure the levels of circulating pro-inflammatory cytokines following TBI. We will then test the therapeutic potential of CARTp as a treatment for TBI by examining its effect on inflammation, blood brain barrier (BBB) permeability, and inflammatory cell infiltration into the injured brain. Finally, we will examine if post-TBI CARTp administration can reduce neuronal loss and improve cognitive outcome. Sex as a biological variable will be assessed. The results from these studies will have implications not only for TBI, as well as for the numerous other diseases in which inflammation is a contributor.