Alpha7 nicotinic acetylcholine receptors and TBI outcome

 描述（由申请人提供）：临床和实验研究均表明，炎症是创伤性脑损伤（TBI）相关病理和神经修复进展的关键因素。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经被详细研究，但全身炎症对TBI结果的贡献还不太确定。已经证明，全身性炎症在很大程度上是由脾介导的，脾受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BBB渗透性、脑水肿并改善TBI后的学习能力，这表明全身炎症在TBI结果中发挥作用。然而，迷走神经活动发挥这些作用的机制尚不清楚。最近的研究表明，这种作用需要脾烟碱α 7烟碱乙酰胆碱受体（α 7 nAChR）。我们建议测试的假设，即损失的α 7烟碱胆碱能信号转导，而增强的α 7 nAChR信号改善，炎症，血脑屏障（BBB）的完整性和认知结果。三个具体目标概述来测试我们的假设。目的1：检测α 7 nAChRs是否调节TBI相关炎症。目的2：检测α 7 nAChR信号转导是否调节TBI后BBB通透性和脑水肿。目的3：确定TBI后给予α 7 nAChR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TBI病理学的新机制，而且将测试基于机制的药物作为TBI治疗的治疗潜力。

 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.