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

钙释放激活钙（CRAC）通道抑制剂在实验性卒中中的作用

• 批准号: 9455186
• 负责人: Midori A Yenari
• 金额: $ 7.67万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9455186
• 关键词: Acute; Adverse effects; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attention; Autoimmune Diseases; Biotechnology; Body part; Brain; Brain Ischemia; Calcineurin; Calcineurin Pathway; Calcineurin inhibitor; Calcium; Calcium Channel; Calcium Channel Inhibition; Calcium Signaling; Cell membrane; Cells; Clinical; Collaborations; Cyclosporine; Developed Countries; Developing Countries; Endoplasmic Reticulum; FK506; Female; Formulation; Health; Immune; Immune response; Immune signaling; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemia; Laboratories; Lead; Leukocytes; Mechanics; Mediating; Microglia; Middle Cerebral Artery Occlusion; Modeling; Mus; Nervous System Trauma; Neurologic; Neurological outcome; Oral; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Principal Investigator; Protein Isoforms; Proteins; Publishing; Regulation; Research; Research Design; Role; STIM1 gene; Source; Stroke; T-Lymphocyte; Tacrolimus; Testing; Therapeutic; Thrombectomy; Time; Toxic effect; Translations; Traumatic Brain Injury; Up-Regulation; Work; acute pancreatitis; brain cell; brain tissue; effective therapy; emergency service responder; immunoreaction; improved; improved outcome; in vivo Model; inhibitor/antagonist; ischemic lesion; male; mast cell; neuroprotection; neutrophil; novel; prevent; programs; response; small molecule inhibitor; stroke treatment; therapeutic target; thrombolysis

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

项目总监/首席调查员(最后、第一、中间)： 项目摘要/摘要 该项目将探索钙释放激活的钙通道(CRAC)作为一种潜在的 中风实验室模型中的治疗靶点。在发达国家，中风是一个重要的健康问题 各国都有，但确切的治疗方法很少，而且还没有可以挽救大脑的治疗方法 因缺血而死亡的细胞。小胶质细胞是大脑的常驻免疫细胞，现在许多研究已经 研究表明，当它们被激活时，它们对中风的结局起到了负面作用。因此，抑制的策略 小胶质细胞的功能可能会被证明是有疗效的。其他实验室最近的工作主要集中在 炎症细胞如T细胞、肥大细胞和中性粒细胞等中的CRAC通道 炎症性疾病，如自身免疫性疾病和急性胰腺炎；然而，很少 关于CRAC通道的研究已经发表，因为它们与大脑中的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，这些抑制剂可以阻断小胶质细胞的激活和 保护大脑免受实验性创伤性脑损伤。这个项目将研究新型的抑制剂。 卒中体内模型中的CRAC通道。暴露于大脑中动脉阻塞的小鼠将 用新型CRAC通道抑制剂治疗，看看这是否会改善神经预后，以及 这是由于预期的抗炎作用。该项目将探索这种化合物是否 将改善雄性和雌性动物实验性中风的结果。 OMB编号0925-0001/0002(08/12版批准至2015年8月31日)页面续格式页面