Defining targets for the treatment of delayed cerebral vasospasm after SAH

描述(由申请人提供)：这项研究的目的是调查中性粒细胞在蛛网膜下腔出血(SAH)后迟发性神经恶化(DND)发展中的作用。该研究策略利用了一种新颖而独特的SAH小鼠模型和一种新描述的可诱导的CXCR2基因敲除小鼠。SAH模型是在NIH科学家发展补助金(K08)机制资助期间开发的。总体假说是SAH后中性粒细胞进入中枢神经系统，中性粒细胞效应机制一旦进入中枢神经系统，DND的发生发展是由中性粒细胞介导的。这项研究的开展将在三个方面推进当前的知识：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 TAT发展中的作用对于理解SAH后阻止中性粒细胞进入中枢神经系统是否将成为治疗的目标以及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。具体目标是：1.明确中性粒细胞在SAH后神经元损伤中的作用。2：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，以确定招募的中性粒细胞在DND中的作用。3：我们将在SAH后的时间点清除中性粒细胞，以确定SAH中性粒细胞损伤的临界时间。这些知识将确定SAH和DND的治疗目标。

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.