Defining targets for the treatment of delayed cerebral vasospasm after SAH

确定SAH后迟发性脑血管痉挛的治疗目标

• 批准号: 8874313
• 负责人: Jose Javier Provencio
• 金额: $ 1.77万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874313
• 关键词: Accounting; Adoptive Transfer; Affect; Aneurysm; Antibodies; Area; Behavioral; Biology; Blood Vessels; Blood coagulation; Brain; Brain Aneurysms; Brain Injuries; Cerebral Ischemia; Cerebrovascular Spasm; Characteristics; Clinical Investigator Award; Clinical Trials; Complication; Data; Deterioration; Development; Funding; Genes; Goals; Grant; Hemorrhage; Hippocampus (Brain); Human; Hypoglycemia; Hypoxia; IL8RB gene; Inflammation; Inflammatory; Injury; Interferons; Interleukin-8B Receptor; Intracranial Aneurysm; Ischemia; Knockout Mice; Knowledge; Laboratories; Lead; Long-Term Potentiation; Mediating; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Myeloid Cells; Neuraxis; Neurologic; Neurologic Dysfunctions; Neuronal Injury; Neurons; Outcome; Pathway interactions; Patients; Performance; Peritoneum; Pharmaceutical Preparations; Poly I-C; Population; Prevention; Recruitment Activity; Research; Research Proposals; Role; Rupture; Ruptured Aneurysm; Scientist; Series; Slice; Spasm; Stroke; Subarachnoid Hemorrhage; Subarachnoid Space; Synapses; Syndrome; Testing; Thioglycolates; Time; Tissues; United States National Institutes of Health; Vasospasm; Wild Type Mouse; Work; base; behavioral outcome; constriction; disability; human disease; improved; migration; mouse development; mouse model; neutrophil; novel; presynaptic; prevent; reconstitution; research study; response; therapy development; treatment strategy; vasoconstriction

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.

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）后延迟性神经功能恶化（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后进入中枢神经系统的募集中性粒细胞和进入中枢神经系统后的中性粒细胞效应机制介导的。本研究的表现将在三个方面推进现有的知识：1)它将表征SAH期间发展的特定神经元变化，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，这对于理解预防SAH后中性粒细胞进入中枢神经系统是否将成为治疗和SAH的目标至关重要。最后，它将有助于回答SAH后给予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：我们将明确中性粒细胞在SAH后神经元损伤中的作用。我们将在SAH后的多个时间点重建CXCR2缺陷小鼠的迁移和具有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。我们将在SAH后的时间点消耗中性粒细胞，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。