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

基本信息

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
项目类别：
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

项目摘要

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

计划主任/首席研究员（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）作为潜力实验室中风模型中的治疗靶标。中风是发达的重大健康问题国家，但确定的治疗很少，没有可用的治疗方法可以挽救大脑细胞死于缺血。小胶质细胞是大脑的常驻免疫细胞，现在许多研究已经表明当激活时，它们会对中风结果负面影响。因此，抑制策略小胶质细胞功能可能证明是治疗性的。其他实验室的最新工作集中于炎性细胞中的CRAC通道，例如T细胞，肥大细胞和中性粒细胞，以及其他炎性疾病，例如自身免疫性疾病和急性胰腺炎；但是，很少工作已在CRAC渠道上发表，因为它们与小胶质细胞或炎症有关缺血性大脑。我们实验室中的初步工作表明，这些抑制剂阻止了小胶质激活和保护大脑免受实验性创伤性脑损伤。该项目将研究新颖的抑制剂 CRAC通道中的体内卒中模型。暴露于脑动脉闭塞的小鼠会用新型的CRAC通道抑制剂治疗，以查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。该项目将探讨该化合物是否将改善男性和雌性动物的实验中风的结果。 OMB No. 0925-0001/0002（Rev. 08/12批准通过8/31/2015）页面延续格式页面