Defining targets for the treatment of delayed cerebral vasospasm after SAH

描述（由申请人提供）：本研究计划的目的是研究中性粒细胞在蛛网膜下腔出血（SAH）后迟发性神经功能恶化（DND）发展中的作用。该研究策略利用了一种新颖独特的SAH小鼠模型和一种新描述的诱导型CXCR2敲除小鼠。SAH模型是在NIH科学家发展资助（K08）机制的资助下开发的。总的假设是，DND的发展是由SAH后进入CNS的中性粒细胞和CNS中的中性粒细胞效应器机制介导的。本研究的开展将在三个方面推进现有知识：1）它将表征SAH期间发生的特定神经元变化，并确定中性粒细胞在神经元损伤中的作用。它将阐明招募的中性粒细胞群体在DND发展中的作用，这对于理解SAH后防止中性粒细胞进入CNS是否是治疗的目标和SAH至关重要。最后，它将有助于回答SAH后给予的阻断中性粒细胞的药物是否对治疗DND有用的问题。具体目的是：1：明确中性粒细胞在SAH后神经元损伤中的作用。第二章：我们将在SAH后的多个时间点重建CXCR2缺陷小鼠中具有迁移和效应功能的中性粒细胞，以确定募集的中性粒细胞在DND中的作用。3：我们将在SAH后的时间点消耗中性粒细胞，以确定SAH中中性粒细胞损伤的关键时间。这些知识将确定SAH和DND的治疗目标。 公共卫生相关性：由于脑动脉瘤出血引起的蛛网膜下腔出血（SAH）可导致永久性残疾，通常由称为迟发性神经功能恶化（DND）的综合征引起。DND发生在蛛网膜下腔出血后4至14天，可导致中风和脑损伤。来自中性粒细胞的炎症已被证明是DND发展的贡献者。确定中性粒细胞对神经元造成损伤的机制对于设计潜在的治疗方法至关重要。此外，中性粒细胞通常不存在于大脑中。蛛网膜下腔出血后，一些中性粒细胞通过破裂的动脉瘤进入大脑。其他的则是稍后才被召唤到大脑中。目前还不清楚是最初的中性粒细胞还是被召唤到大脑中的中性粒细胞在DND的发展中更重要。这一点很重要，因为我们不太可能阻止中性粒细胞在动脉瘤破裂时进入大脑。因此，基于这种策略的治疗取决于我们对这种生物学的理解。

DESCRIPTION (provided by applicant): The goal of this research proposal is to investigate the role of neutrophils in the development of delayed neurologic deterioration (DND) after subarachnoid hemorrhage (SAH). The research strategy utilizes a novel and unique mouse model of SAH and a newly described inducible CXCR2 knockout mouse. The model of SAH was developed during funding from an NIH scientist development grant (K08) mechanism. The overall hypothesis is that the development of DND is mediated by recruited neutrophils entering the CNS after SAH and from neutrophil effector mechanisms once in the CNS. Performance of this research will advance current knowledge in three ways: 1) It will characterize the specific neuronal changes developed during SAH and determine the role of neutrophils in neuronal injury. It will clarify the role of the recruited neutrophil population in the development of DND tat is critical to understanding whether prevention of neutrophil entry into the CNS after SAH will be a target for treatment, and SAH. And finally it will help answer the question of whether medications administered after SAH that block neutrophils will be useful to treat DND. The Specific Aims are: 1: We will define the role of neutrophils in neuronal damage after SAH.. 2: We will reconstitute migration and effector function-competent neutrophils in CXCR2 deficient mice at multiple time points AFTER SAH to define the role of the recruited neutrophils in DND. 3: We will deplete neutrophils at time points after the SAH to define the critical times for neutrophil damage in SAH. This knowledge will identify targets for treatment in SAH and DND. PUBLIC HEALTH RELEVANCE: Subarachnoid hemorrhage (SAH) due to bleeding from a brain aneurysm can lead to permanent disability often caused by a syndrome called delayed neurologic deterioration (DND). DND occurs 4 to 14 days after a subarachnoid hemorrhage and can lead to stroke and brain damage. Inflammation from neutrophils has been shown to be a contributor to the development of DND. Determining the mechanism by which neutrophils cause damage to neurons is critical to devising potential treatments. Additionally, neutrophils are usually not present in the brain. After SAH, some neutrophils get in to the brain through the burst aneurysm. Others are called into the brain later. It is still unclear whether the initial grop of neutrophils or the ones called into the brain are more important in the development of DND. This is important because it is unlikely that we can prevent neutrophils that enter the brain during the rupture of the aneurysm. Therefore, treatments based on this strategy depend on our understanding of this biology.