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）：脑海绵状血管瘤（CCMs）是最常见的脑血管畸形，在人群中检出率约为每10万人0.6例。CCMs被认为是家族性或散发性病例，其特征是单个或多簇增大的毛细血管样通道，单层内皮细胞，无脑实质介入。脑内皮屏障成分的特异性改变最终导致血管高通透性、红细胞外渗和脑实质炎症反应。CCMs患者可能表现为癫痫发作、局灶缺损或非特异性头痛，最常见的并发症是出血性中风。尽管在确定遗传性CCMs中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致病机制在很大程度上仍然未知。该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脑海绵状血管瘤3型。特别地，该建议将处理涉及组织TJ复合体的多顺序事件。重点介绍信号分子CCM3蛋白与肌动蛋白细胞骨架蛋白cortnn之间的相互作用如何影响脑内皮紧密连接复合物的组织和稳定性。具体而言，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后果；b) CCM3-接触相互作用在建立ZO-1与肌动蛋白细胞骨架以及ZO-1与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相关的机制的新信息，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的治疗策略来恢复血管的高渗透性。