Calcium release-activated calcium (CRAC) channel inhibitors in experimental stroke

项目负责人/主要研究者（最后一名、第一名、中间名）： 项目概要/摘要 本项目将探讨钙释放激活的钙通道（CRAC）作为一种潜在的 在实验室中风模型中的治疗目标。中风是发达国家的一个重大健康问题， 国家，但确定的治疗方法很少，没有治疗方法可以挽救大脑 因局部缺血而死亡的细胞小胶质细胞是大脑的常驻免疫细胞，现在许多研究都表明， 当它们被激活时，它们会对中风的结果产生负面影响。因此，抑制 小胶质细胞的功能可以证明是有治疗作用的。其他实验室最近的工作集中在以下方面的作用： 炎性细胞如T细胞、肥大细胞和嗜中性粒细胞中的CRAC通道，以及其他 炎症性疾病，如自身免疫性疾病和急性胰腺炎;然而， 已经发表了关于CRAC通道的工作，因为它们与小胶质细胞或炎症有关。 脑缺血我们实验室的初步工作表明，这些抑制剂阻断了小胶质细胞的激活， 保护大脑免受实验性脑损伤。该项目将研究新型的抑制剂， 中风的体内模型中的CRAC通道。暴露于大脑中动脉闭塞的小鼠将 用新型CRAC通道抑制剂治疗，看看这是否会改善神经系统的结果， 这是由于预期的抗炎作用。这个项目将探索这种化合物 将改善雄性和雌性动物实验性中风的结果。 OMB编号0925-0001/0002（2012年8月批准至2015年8月31日修订版）页码续页格式页码

Program Director/Principal Investigator (Last, First, Middle): Project Summary/Abstract This project will explore calcium-release-activated calcium channels (CRAC) as a potential therapeutic target in a laboratory stroke model. Stroke is a significant health problem in developed nations, but definitive treatments are few, and no treatments are available which can rescue brain cells dying from ischemia. Microglia are the brain's resident immune cell, and many studies have now shown that when activated, they contribute negatively to stroke outcome. Thus, strategies to inhibit microglial functions could prove therapeutic. Recent work by other labs has focused on the role of CRAC channels in inflammatory cells such as T cells, mast cells and neutrophils, and other inflammatory conditions such as autoimmune disease and acute pancreatitis; however, very little work has been published on CRAC channels as they pertain to microglia or inflammation in the ischemic brain. Preliminary work in our lab showed that these inhibitors block microglial activation and protect the brain from experimental traumatic brain injury. This project will study novel inhibitors of CRAC channels in an in vivo model of stroke. Mice exposed to middle cerebral artery occlusion will be treated with novel CRAC channel inhibitors to see if this will improve neurological outcomes, and if this is due to an anticipated anti-inflammatory effect. This project will explore whether this compound will improve outcome in experimental stroke in both male and female animals. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page