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：
8166264
负责人：
ANUSKA V. ANDJELKOVIC-ZOCHOWSKA
金额：
$ 23.33万
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/8166264
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. PUBLIC HEALTH RELEVANCE: Normally, the brain is protected from changes in the bloodstream by the blood-brain barrier situated at the brain blood vessels. Defects in that barrier may be important for developing stroke, epilepsy and other neurological diseases. One disease that affects the blood-brain barrier is cerebral cavernous malformation-3. This vascular malformation is characterized by thin-walled vascular cavities that may rupture. The purpose of this study is to highlight the molecular mechanisms underlying vessel hyperpermeability in this condition. This may provide a foundation for developing novel therapeutic strategies to lessen the impact of this disease as well as other neurological conditions that affect the blood-brain barrier.

描述（由申请人提供）：脑海绵状血管瘤 (CCM) 是最常见的脑血管畸形，在人群中的检出率约为每 100,000 人 0.6 例。 CCM 被认为是家族性或散发性病例，其特征是单个或多簇扩大的毛细血管样通道，具有单层内皮，且无脑实质介入。脑内皮屏障成分发生特定改变，最终导致血管通透性过高、红细胞外渗和脑实质炎症反应。 CCM 患者可能会出现癫痫发作、局部功能障碍或非特异性头痛，最常见的并发症是出血性中风。尽管在定义遗传性 CCM 涉及的基因突变方面已经做出了巨大的努力，但导致血管通透性过高的细胞内和细胞间致病机制仍然很大程度上未知。拟议的研究旨在阐明维持脑内皮屏障完整性的关键分子事件，以及这些事件如何改变 3 型脑海绵状血管瘤。特别是，该提案将解决 TJ 复合体组织中涉及的多序列事件。它将重点介绍信号分子 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）CCM3病理条件下CCM3缺失对TJ复合物/肌动蛋白细胞骨架相互作用的功能和形态学影响；b）CCM3-cortactin相互作用在建立ZO-1和ZO-1之间稳定相互作用中的作用肌动蛋白细胞骨架以及 ZO-1 和 Claudin-5。总的来说，这些研究将提供与维持脑内皮屏障机制相关的新信息，该机制不仅与 CCM3 相关，而且与多种疾病状态相关。希望这将有助于阐明恢复血管通透性过高的新治疗策略。公众健康相关性：通常，位于脑血管处的血脑屏障可以保护大脑免受血流变化的影响。该屏障的缺陷可能对中风、癫痫和其他神经系统疾病的发生很重要。影响血脑屏障的一种疾病是脑海绵状血管瘤3。这种血管畸形的特点是薄壁血管腔可能破裂。本研究的目的是强调这种情况下血管渗透性过高的分子机制。这可能为开发新的治疗策略奠定基础，以减轻这种疾病以及影响血脑屏障的其他神经系统疾病的影响。