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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

目前，脑出血（ICH）是一种常见且往往致命的卒中亚型，尚无有效的治疗方法。ICH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亚家族，包括两个成员PDGFR-α和PDGFR-β JDGFR在脑中的各种细胞类型中表达并参与平滑肌表型变化。我们先前的研究发现，PDGFR抑制剂Gleevec抑制PDGFR可减少ICH小鼠模型的脑水肿和BBB渗漏。其他人也报道PDGFR与缺血性脑损伤中的BBB破坏相关。然而，PDGFR相关的血脑屏障损伤的机制仍不清楚，并且从未研究过ICH损伤中平滑肌表型变化的作用。我们的初步数据显示，格列卫诱导的脑出血后BBB保护作用与抑制p38 MAPK通路有关。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中肌源性张力的丧失和平滑肌表型蛋白的变化;格列卫治疗可拮抗这些变化。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后的神经学结局。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）。以下研究旨在验证我们的假设：目的1将确定脑出血后给予Gleevec的神经血管保护作用，包括BBB完整性，平滑肌表型变化和长期神经功能结局。目的2探讨PDGFR-p38-MAPK-MAPKAPK 2-LIMK 1通路在ICH诱导的血脑屏障破坏中的作用。目的3探讨格列卫对SAH和TBI模型的神经血管保护作用。我们的长期目标是探索PDGFR在神经血管损伤中的重要性，以便将来作为出血性脑损伤患者的潜在治疗靶点进行评估