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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：
8993927
负责人：
Jiping Tang
金额：
$ 19.46万
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/8993927
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 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 Vascular Smooth Muscle actin depolymerizing factor cell type cerebral artery cofilin disability effective therapy improved inhibitor/antagonist member mortality mouse model neurovascular neurovascular injury neurovascular unit novel outcome forecast prevent protective effect research clinical testing therapeutic target treatment strategy vasogenic edema

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

脑出血是一种常见且常常致命的脑卒中亚型，目前尚无有效的治疗方法。脑出血后继发性脑损伤包括脑水肿、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。PDGFRs在大脑的各种细胞类型中表达，并参与平滑肌表型的改变。我们之前的研究发现，PDGFR抑制剂格列卫抑制PDGFR，可以减少脑出血小鼠模型的脑水肿和血脑屏障渗漏。其他人也报道PDGFR与缺血性脑损伤中的血脑屏障破坏有关。然而，pdgfr相关血脑屏障损伤的机制尚不清楚，平滑肌表型改变在脑出血损伤中的作用从未被研究过。我们的初步数据显示，格列卫诱导的脑出血后血脑屏障保护与p38 MAPK通路的抑制有关。我们的初步研究也取得了突破性的发现，ICH导致血肿附近脑动脉肌原性张力的丧失和平滑肌表型蛋白的改变；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改变来减少血脑屏障破坏，从而改善脑出血后的神经预后。格列卫治疗还可以预防其他类型出血性脑损伤的神经血管损伤，包括蛛网膜下腔出血（SAH）和创伤性脑损伤（TBI）。我们提出以下研究来验证我们的假设：目的1将确定脑出血后给予格列卫的神经血管保护作用，包括血脑屏障完整性、平滑肌表型改变和长期神经预后。目的2将研究PDGFR-p38- MAPK-MAPKAPK2-LIMK1通路在ich诱导的血脑屏障破坏中的作用。目的3将确定格列卫治疗在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，以便将来评估其作为出血性脑损伤患者的潜在治疗靶点