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

• 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
• 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

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）：脑海绵状畸形（CCM）是最常见的脑血管畸形，在人群中以每100,000份约0.6的速度检测到。 CCM被公认为是家族性或零星的病例，其特征是单层内皮层的毛细血管样通道的多个簇中的单个簇，而无需干预脑实质。脑内皮屏障成分有特定的改变，最终导致血管过敏性，红细胞的渗出以及脑实质中的炎症反应。 CCM的患者可能出现癫痫发作，局灶性缺陷或非特异性头痛，并且最常见的并发症是出血性中风。尽管在定义与遗传CCMS相关的基因突变方面做出了巨大的努力，但导致血管过度过度性的负责的细胞内和细胞间致病机制仍然很大程度上尚不清楚。拟议的研究旨在阐明关键分子事件在维持脑内皮屏障的完整性以及如何改变脑海绵状畸形3型3中。特别是，该建议将解决与TJ复合物组织组织有关的多次事件。它将突出信号分子，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内皮紧密连接络合物的组织和稳定性。具体而言，将评估以下目标：a）CCM3在CCM3病理学和B）CCM3-Cortactin相互作用在建立ZO-1和actocin cytoskeleton and actacin cytoskeleton and zo-1和claudaudin-5之间的作用中CCM3缺乏对TJ复合物/肌动蛋白细胞骨架相互作用的功能和形态后果。总的来说，这些研究将提供与维持脑内皮屏障涉及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新型的治疗策略，以恢复血管过敏性。 公共卫生相关性：通常，大脑受到脑血管上的血脑屏障的保护，免受血液的变化。该障碍的缺陷对于发展中风，癫痫和其他神经系统疾病可能很重要。一种影响血脑屏障的疾病是脑海绵状畸形3。这种血管畸形的特征是可能破裂的薄壁血管腔。这项研究的目的是强调在这种情况下血管过敏性的分子机制。这可能为制定新的治疗策略提供基础，以减少该疾病的影响以及其他影响血脑屏障的神经系统疾病。