格列卫通过抑制 PDGFR 保护神经血管单位-猫眼课题宝

格列卫通过抑制 PDGFR 保护神经血管单位

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

项目状态：

未结题

起止时间：

至

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

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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

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