Gleevec Protects Neurovascular Unit by Inhibition of PDGFR

格列卫通过抑制 PDGFR 保护神经血管单位

基本信息

批准号：
8661425
负责人：
Jiping Tang
金额：
$ 19.47万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8661425
关键词：
Accounting Address Affect Antineoplastic Agents Astrocytes Behavioral Blood - brain barrier anatomy Blood Vessels Brain Brain Edema Brain Injuries Brain hemorrhage Capillary Endothelial Cell Cerebral Edema Cerebral hemisphere hemorrhage Cerebrovascular Spasm Cerebrum Clinical Data Edema Endothelial Cells Endothelium Evaluation Extravasation FDA approved Foundations Future Gap Junctions Gleevec Goals Hematoma In Vitro Individual Injury Intercellular Junctions Investigation Ischemic Brain Injury LIM Domain Kinase 1 Left MAP Kinase Gene MAPK1 gene MAPK14 gene MAPKAPK2 gene Magnetic Resonance Imaging Mediating Modeling Morbidity - disease rate Mus Nature Neurologic Neurological outcome Neurons Outcome Pathology Pathway interactions Patients Pericytes Phenotype Phosphorylation Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Play Proteins Publishing Receptor Protein-Tyrosine Kinases Receptor Signaling Reporting Research Role Signal Pathway Smooth Muscle Smooth Muscle Myocytes Stress Stress Fibers Stroke Subarachnoid Hemorrhage Testing Traumatic Brain Injury United States actin depolymerizing factor cell type cerebral artery cofilin disability effective therapy improved inhibitor/antagonist member mortality mouse model neurovascular unit novel outcome forecast prevent protective effect research clinical testing therapeutic target treatment strategy

项目摘要

At present, there is no effective treatment for intracerebral hemorrhage (ICH), a common and often fatal stroke subtype. Secondary brain injury after ICH is known to involve brain edema, disruption ofthe blood brain barrier (BBB), and neurological deficits. Platelet derived growth factor receptors (PDGFRs) are a subfamily of tyrosine kinase receptors including two members, PDGFR-a and PDGFR-p. PDGFRs are expressed in various cell-types in the brain and participate in smooth muscle phenotype changes. Our previous study has found that PDGFR suppression by Gleevec, a PDGFR inhibitor, reduces brain edema and BBB leakage in a mouse model of ICH. Others also reported that PDGFR is associated with BBB disruption in ischemic brain injury. However the mechanisms of PDGFR-associated BBB damage remain unclear and the role of smooth muscle phenotype changes in ICH injury has never been studied. Our preliminary data showed that Gleevec-induced BBB protection after ICH is associated with inhibition of p38 MAPK pathway. Our preliminary study also made a groundbreaking discovery that ICH results the loss of myogenic tone and the changes of smooth muscle phenotype proteins in the cerebral arteries near the hematoma; Gleevec treatment antagonizes these changes. Therefore, we hypothesize that PDGFR-suppression with Gleevec will reduce BBB disruption via protecting intercellular junctions and preventing smooth muscle phenotype changes thus improving neurological outcome after ICH. Gleevec treatment will also prevent neurovascular damage in other types of hemorrhagic brain injury including subarachnoid hemorrhage (SAH) and traumatic brain injury (TBI). The following studies are proposed to test our hypothesis: Aim 1 will determine the neurovascular protective effect of Gleevec administration after ICH, including BBB integrity, smooth muscle phenotype changes and long-term neurological outcomes. Aim 2 will investigate the role of PDGFR-p38- MAPK-MAPKAPK2-LIMK1 pathway in ICH-induced BBB disruption. Aim 3 will determine the neurovascular protective effect of Gleevec treatment in SAH and TBI models. Our long-term goal is to explore the importance of PDGFR involved in neurovascular injury for future evaluation as a potential therapeutic target against hemorrhagic brain injury in patients

目前，脑出血（ICH）是一种常见且往往致命的中风亚型，尚无有效的治疗方法。已知 ICH 后的继发性脑损伤涉及脑水肿、血脑屏障 (BBB) 破坏和神经功能缺损。血小板衍生生长因子受体 (PDGFR) 是酪氨酸激酶受体的一个亚家族，包括两个成员：PDGFR-a 和 PDGFR-p。 PDGFR 在大脑中的各种细胞类型中表达，并参与平滑肌表型的变化。我们之前的研究发现，PDGFR 抑制剂格列卫（Gleevec）对 PDGFR 的抑制可减少 ICH 小鼠模型的脑水肿和 BBB 渗漏。其他人还报道称，PDGFR 与缺血性脑损伤中的 BBB 破坏有关。然而，PDGFR 相关 BBB 损伤的机制仍不清楚，平滑肌表型变化在 ICH 损伤中的作用也从未被研究过。我们的初步数据表明，格列卫在 ICH 后诱导的 BBB 保护与 p38 MAPK 通路的抑制有关。我们的初步研究还取得了突破性的发现，即ICH导致血肿附近脑动脉肌源性张力丧失和平滑肌表型蛋白变化；格列卫治疗可以对抗这些变化。因此，我们假设格列卫抑制 PDGFR 将通过保护细胞间连接和防止平滑肌表型变化来减少 BBB 破坏，从而改善 ICH 后的神经系统结果。格列卫治疗还可预防其他类型出血性脑损伤中的神经血管损伤，包括蛛网膜下腔出血 (SAH) 和创伤性脑损伤 (TBI)。提出以下研究来检验我们的假设：目标 1 将确定 ICH 后格列卫给药的神经血管保护作用，包括血脑屏障完整性、平滑肌表型变化和长期神经学结果。目标 2 将研究 PDGFR-p38-MAPK-MAPKAPK2-LIMK1 通路在 ICH 诱导的 BBB 破坏中的作用。目标 3 将确定格列卫治疗 SAH 和 TBI 模型中的神经血管保护作用。我们的长期目标是探索 PDGFR 参与神经血管损伤的重要性，以便未来评估其作为患者出血性脑损伤的潜在治疗靶点