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.
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.