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The mechanism of blood brain barrier impairment in cerebral cavernous malformatio

脑海绵状血管瘤血脑屏障损伤的机制

基本信息

批准号：
8320860
负责人：
ANUSKA V. ANDJELKOVIC-ZOCHOWSKA
金额：
$ 19.44万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8320860
关键词：
Actins Address Adherens Junction Affect Affinity Area Binding Proteins Blood - brain barrier anatomy Blood Circulation Blood Vessels Blood capillaries Brain Brain Vascular Malformation Brain hemorrhage CCM1 gene Cadherins Catalytic Domain Cavernous Hemangioma Cavernous Malformation Cell Fraction Cells Cerebrum Complex Complication Cytoskeleton Cytosol Defect Development Disease Endothelial Cells Endothelium Epilepsy Erythrocytes Event Extravasation Fluorescein-5-isothiocyanate Focal Seizure Foundations Gene Mutation Headache Hemangioma Herpes zoster disease Impairment In Vitro Inflammatory Response Inherited Intercellular Junctions Inulin Lead Lesion Link Maintenance Membrane Modality Molecular Molecular Weight Nerve Degeneration Neurologic Pathology Patients Pattern Permeability Phosphoric Monoester Hydrolases Phosphotransferases Play Population Process Production Property Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Proteins Proteomics Regulation Role Rupture Signal Transduction Signaling Molecule Smooth Muscle Myocytes Stroke Structure Tight Junctions Tracer angiogenesis base capillary cerebrovascular claudin-1 protein design human EMS1 protein human tissue in vivo malformation mutant nervous system disorder novel novel therapeutics scaffold

项目摘要

DESCRIPTION (provided by applicant): Cerebral cavernous malformations (CCMs) are the most common brain vascular malformations and are detected in the population at a rate of approximately 0.6 per 100,000. Recognized as familial or sporadic cases, CCMs are characterized as single of multi cluster of enlarged capillary-like channels with a single layer of endothelium and without intervening brain parenchyma. There are specific alterations in brain endothelial barrier components that ultimately lead to vascular hyperpermeability, extravasation of red cells and inflammatory response in brain parenchyma. Patients with CCMs may present with seizures, focal deficits, or nonspecific headaches and as most common complication is hemorrhagic stroke. Although significant effort has been made in defining the genes mutations involved in inherited CCMs, the intra- and intercellular pathogenic mechanisms responsible for vascular hyperpermeability are still largely unknown. The proposed study is designed to elucidate critical molecular events in maintaining the integrity of the brain endothelial barrier and how these are altered cerebral cavernous malformation type 3. In particular, the proposal will address the multisequential events involved in organization of the TJ complex. It will highlight how the interaction between signaling molecules, CCM3 protein and an actin cytoskeleton protein, cortactin, affect the organization and stability of brain endothelial tight junctional complex. Specifically, the following objectives will be evaluated: a) the functional and morphological consequence of CCM3 absence on TJ complex/actin cytoskeleton interactions in conditions of CCM3 pathology and b) the role of CCM3-cortactin interaction in establishing stable interactions between ZO-1 and the actin cytoskeleton and ZO-1 and claudin-5. Collectively, these studies will provide new information related to the mechanisms involved in maintaining the brain endothelial barrier that is relevant not only to CCM3 but also to multiple disease states. Hopefully, this will help to elucidate novel therapeutic strategies to restore vascular hyperpermeability.

描述(申请人提供)：脑海绵状血管畸形(CCM)是最常见的脑血管畸形，在人群中以大约每10万人中0.6人的比率被发现。CCM被认为是家族性或散发性病例，其特点是单个或多个增大的毛细血管样通道，内皮细胞单层，不干预脑实质。脑内皮细胞屏障成分有特定的变化，最终导致血管高通透性、红细胞外溢和脑实质的炎症反应。CCM患者可能会出现癫痫发作、局灶性缺陷或非特异性头痛，最常见的并发症是出血性中风。尽管在确定遗传性CCM涉及的基因突变方面已经做出了重大努力，但导致血管高通透性的细胞内和细胞间的致病机制仍然很大程度上是未知的。这项拟议的研究旨在阐明维持脑内皮细胞屏障完整性的关键分子事件以及这些事件是如何改变脑3型海绵状畸形的。特别是，该研究将解决参与TJ复合体组织的多序列事件。它将强调信号分子CCM3蛋白和肌动蛋白细胞骨架蛋白Cortactin之间的相互作用如何影响脑内皮紧密连接复合体的组织和稳定性。具体来说，将评估以下目标：a)在CCM3病理条件下，CCM3缺失对TJ复合体/肌动蛋白细胞骨架相互作用的功能和形态影响，以及b)CCM3-Cortactin相互作用在建立ZO-1和肌动蛋白细胞骨架与ZO-1和claudin-5之间稳定相互作用中的作用。总的来说，这些研究将提供与维持脑内皮屏障的机制有关的新信息，这不仅与CCM3有关，而且与多种疾病状态有关。希望这将有助于阐明恢复血管高通透性的新治疗策略。