Alpha7 nicotinic acetylcholine receptors and TBI outcome

 描述(由申请人提供)：临床和实验研究都表明，炎症在创伤性脑损伤(TBI)相关病理和神经修复的进展中起关键作用。不受控制的炎症可能导致组织损伤加剧，并可能阻碍修复过程。虽然起源于受损大脑的局部炎症的作用已被详细研究，但全身炎症对脑外伤预后的影响尚不清楚。已经证明，全身炎症在很大程度上是由脾介导的，而脾则由迷走神经的传出成分调节。先前的研究表明，刺激迷走神经可以降低脑损伤后血脑屏障通透性、脑水肿和改善学习能力，提示全身炎症在脑损伤预后中起作用。然而，迷走神经活动发挥这些效应的机制(S)尚不清楚。最近的研究表明，这种作用需要脾的烟碱型α7烟碱型乙酰胆碱受体(Alpha7nAChR)。我们建议检验这一假设，即α7烟碱能胆碱能信号的丢失会恶化，而α7nAChR信号的增强会改善炎症、血脑屏障(BBB)完整性和认知结果。为了验证我们的假设，我们提出了三个具体目标。目的：研究α7nAChRs是否调节脑损伤相关的炎症反应。目的2：探讨α7nAChR信号对脑挫伤后血脑屏障通透性和脑水肿的调节作用。目的3：确定脑损伤后应用α7nAChR激动剂是否改善学习和记忆，并提供神经保护。这些研究的结果不仅将测试脑损伤病理基础的新机制，而且将测试基于机制的药物作为治疗脑损伤的治疗潜力。

 DESCRIPTION (provided by applicant): Both clinical and experimental studies have suggested that inflammation is a key player in the progression of traumatic brain injury (TBI)-associated pathologies and neural repair. Uncontrolled inflammation can lead to exacerbated tissue damage and can hinder the repair process. While the role of local inflammation originating in the injured brain has been examined in some detail, the contribution of systemic inflammation to TBI outcome is less established. It has been demonstrated that systemic inflammation is mediated, in large part, by the spleen, which is regulated by the efferent component of the vagus nerve. Previous studies have shown that stimulation of the vagus nerve can reduce BBB permeability, cerebral edema and improve learning after TBI, suggesting a role for systemic inflammation in TBI outcome. However, the mechanism(s) by which vagus nerve activity exerts these effects is not understood. Recent studies have shown that this effect requires splenic nicotinic alpha 7 nicotinic acetylcholine receptor (alpha7nAChR). We propose to test the hypothesis that loss of alpha 7 nicotinic cholinergic signaling worsens, while augmentation of alpha7nAChR signaling improves, inflammation, blood-brain barrier (BBB) integrity and cognitive outcome. Three Specific Aims are outlined to test our hypothesis. Aim1: To examine if alpha7nAChRs regulate TBI-associated inflammation. Aim 2: To test if alpha7nAChR signaling regulates BBB permeability and cerebral edema following TBI. Aim 3: To determine if post-TBI administration of alpha7nAChR agonists improves learning and memory and offers neuroprotection. The results from these studies will not only test a novel mechanism underlying TBI pathology, but will test the therapeutic potential of mechanism-based agents as a treatment for TBI.