The role of CD147 in ischemic inflammation and brain injury

CD147在缺血性炎症和脑损伤中的作用

• 批准号: 8877660
• 负责人: Guohong Li
• 金额: $ 31.72万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8877660
• 关键词: Acute; Acute myocardial infarction; Adoptive Transfer; Alzheimer' s Disease; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Atrophic; Blocking Antibodies; Blood Circulation; Blood Vessels; Brain; Brain Injuries; CD147 antigen; Cardiovascular Diseases; Cause of Death; Cells; Cerebral Ischemia; Cyclophilin A; Cyclophilins; Data; Development; Excision; Experimental Autoimmune Encephalomyelitis; Functional disorder; Health; ITGAM gene; Immune; Immune System Diseases; Immune response; Immunoglobulin G; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Investigation; Ischemic Stroke; Leukocytes; Lung; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Membrane Glycoproteins; Middle Cerebral Artery Occlusion; Modeling; Molecular; Multiple Sclerosis; Mus; Myocardial; Pathogenesis; Pathology; Patients; Peripheral; Play; Pneumonia; Rattus; Receptor Signaling; Recovery of Function; Reporting; Risk; Role; Secondary to; Severity of illness; Small Interfering RNA; Source; Spleen; Stroke; Study Section; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; base; cell type; clinically relevant; cytokine; disability; extracellular; human disease; insight; intravenous injection; leukocyte activation; macrophage; migration; monocyte; nervous system disorder; novel; post stroke; protein expression; response; therapeutic target

DESCRIPTION (provided by applicant): This R01 application aims to investigate novel roles of CD147 in stroke-induced peripheral immune dysfunction and stroke pathology. Recent studies, including our own, favor an important notion that stroke-induced peripheral immune dysfunction not only predisposes patients to post-stroke infections (particularly pneumonia) but also contributes to secondary brain damage by exacerbating and perpetuating inflammatory response in the post-ischemic brain. The spleen has emerged as a novel target that mediates the peripheral immune response after stroke. Based on the novel findings discussed in the Preliminary Studies section, we propose the central hypothesis that CD147 acts as a novel key regulator of the splenic response to focal cerebral ischemia and that contributes importantly to secondary brain damage after stroke. Specifically, we propose that spleen monocytes play a critical role in stroke- mediated brain injury through a novel CD147 mechanism. Specific Aim 1 will test the hypothesis that CD147 contributes importantly to ischemic inflammation and brain injury and thus therapeutic blockade of CD147 provides neurovascular protection in ischemic stroke. Aim 1a: We will investigate whether therapeutic targeting of CD147 provides neurovascular protection in ischemic stroke. Anti-CD147 function-blocking antibodies will be given by intravenous injection at clinically relevant time points. Aim 1b: We will investigate the cellular and molecular mechanisms by which CD147 contributes to stroke injury, with a focus on examining brain leukocyte infiltration, BBB disruption, and the splenic inflammatory activation after stroke. Aim 1c: We will determine whether therapeutic targeting of CD147 has long-term beneficial effects on functional recovery after stroke. Specific Aim 2 will test the hypothesis tha CD147 is a key mediator of the spleen's immune response and contribution to ischemic stroke through spleen inflammatory monocytes. Aim 2a: We will determine the cell-type specific expression of CD147 in the spleens of mice subjected to tMCAO and the role of CD147 in inflammatory activation of splenic immunocytes (particularly monocytes, T cells) after stroke. Aim 2b: By adoptive transfer of spleen monocytes into splenectomized mice, we will determine whether spleen inflammatory monocytes contribute importantly to stroke injury. To selectively target CD147 on spleen monocytes, siRNA knockdown technique will be used. Aim 2c: We will determine the effects of therapeutic targeting of CD147 on stroke-induced splenic atrophy and poststroke infections. These studies will reveal novel roles of CD147 in the spleen's immune response and contribution to cerebral ischemia, and the findings may have potential implications for developing novel treatments for stroke.

描述（由申请人提供）：此R01应用程序旨在研究CD147在中风诱导的外周免疫功能障碍和中风病理学中的新作用。最近的研究，包括我们自己的研究，偏爱中风诱导的外周免疫功能障碍不仅使患者遭受中风后感染（尤其是肺炎），而且还通过加剧脑损伤并通过加剧后的脑损伤和炎症后的炎症反应导致脑损伤。脾脏已成为一个新的靶标，它介导了中风后的外周免疫反应。基于初步研究部分讨论的新发现，我们提出了一个中心假设，即CD147充当对局灶性脑缺血的脾脏反应的新型关键调节剂，这对中风后的继发性脑损伤有效。具体而言，我们建议脾脏单核细胞通过一种新型的CD147机制在中风介导的脑损伤中起关键作用。具体目标1将检验CD147对缺血性炎症和脑损伤的重要贡献的假设，因此CD147的治疗阻滞可提供缺血性中风的神经血管保护。 AIM 1A：我们将研究CD147的治疗靶向是否提供缺血性中风的神经血管保护。抗CD147功能阻断抗体将通过临床相关时间点的静脉注射给出。 AIM 1B：我们将研究CD147导致中风损伤的细胞和分子机制，重点是检查脑白细胞浸润，BBB破坏和中风后的脾脏炎症激活。 AIM 1C：我们将确定CD147的治疗靶向是否对中风后的功能恢复具有长期有益作用。具体目标2将检验CD147假设是脾脏免疫反应和通过脾炎症单核细胞对缺血性中风的贡献的关键介体。 AIM 2A：我们将确定受TMCAO的小鼠脾脏的细胞类型特异性表达，以及中风后CD147在脾脏免疫细胞（尤其是单核细胞，T细胞）炎症激活中的作用。 AIM 2B：通过将脾单核细胞的收养转移到脾切除小鼠中，我们将确定脾脏炎症单核细胞是否对中风损伤有重要作用。为了有选择地靶向脾单核细胞上的CD147，将使用siRNA敲低技术。 AIM 2C：我们将确定CD147治疗靶向对中风引起的脾萎缩和中风后感染的影响。这些研究将揭示CD147在脾脏的免疫反应和对脑缺血的贡献中的新作用，并且发现可能对开发中风的新疗法具有潜在的影响。