Molecular mechanism mediating apicobasal brain endothelial cells polarity in cerebral cavernous malformation type 3-lesion

脑海绵状血管瘤3型病变中顶基底层脑内皮细胞极性的分子机制

• 批准号: 10526456
• 负责人: ANUSKA V. ANDJELKOVIC-ZOCHOWSKA
• 金额: $ 41.95万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10526456
• 关键词: Adherens Junction; Affect; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Brain Vascular Malformation; Brain hemorrhage; CCM1 gene; Cell Polarity; Cells; Clinical Research; Collaborations; Complex; Connexin 43; Crosslinker; DNA Sequence Alteration; Data; Defect; Development; Disease; Dislocations; Endothelial Cells; Endothelium; Epilepsy; Erythrocytes; Event; Extravasation; Foundations; Genes; Golgi Apparatus; Hematological Disease; Hemorrhage; In Vitro; Inherited; Lead; Lesion; Link; Maintenance; Mediating; Mesenchymal; Modality; Modeling; Molecular; Mus; Mutation; Nerve Degeneration; Neurologic; PARD6A gene; Pathogenicity; Pathologic; Pattern; Permeability; Phenotype; Population; Process; Protein Isoforms; Proteins; Regulation; Role; Rupture; Signal Pathway; Site; Stimulus; Stroke; Structure; TP53 gene; Thinness; Tight Junctions; Vascular Permeabilities; Venous; angiogenesis; base; blood-brain barrier permeabilization; brain endothelial cell; brain malformation; brain parenchyma; capillary bed; cerebral cavernous malformations; design; experimental study; in vivo; insight; malformation; mouse model; mutant; nervous system disorder; neuroinflammation; novel therapeutic intervention; novel therapeutics; planar cell polarity; polarized cell; receptor; response; screening; vascular abnormality; vascular injury

Brain vascular malformations and blood-brain barrier defects represent important substrates for developing stroke, epilepsy and other neurological diseases. The most common type of brain malformation closely associated with stroke are the cerebral cavernous malformations (CCMs), which affect approximately 0.5% of the population. Recognized as inherited and sporadic, CCMs are characterized as a single or multi-cluster of enlarged capillary-like channels with a single layer of endothelium and without intervening brain parenchyma. There are specific alterations in the brain endothelial barrier components that ultimately lead to vascular hyperpermeability, extravasation of red cells and a neuroinflammatory response. Although significant progress has been made in defining the genetic mutations involved in the inherited CCM3 form, the intra- and intercellular pathogenic mechanisms responsible for vascular injury are still largely unknown. One robust change in brain endothelial cell phenotype is a defect in cell polarity that affects the cell response to environmental stimuli and may progress the vascular injury. The proposed study is designed to elucidate critical molecular events involved in regulation of apicobasal polarity in CCM3 conditions. It will highlight the link between CCM3 and the cell polarity complex Par3/Par6/aPKC, identified by our screening analysis to be highly impacted by loss of CCM3 function in brain endothelial cells. Specifically, it will evaluate structural and functional alterations in the apicobasal polarity of brain endothelial cells in conditions of modified expression of CCM3 and CCM3 lesions. Collectively, these studies will provide information related to potential causes of leakiness and hemorrhage in CCM3 lesions, offer the new insights into the maintenance of brain endothelial barrier that is relevant also to multiple disease states and will, hopefully, elucidate novel therapeutic strategies to restore vascular permeability.

脑血管畸形和血脑屏障缺陷是重要的 中风、癫痫和其他神经系统疾病的发生基质。最 与中风密切相关的常见脑畸形类型是脑 海绵状血管畸形（CCM），影响约0.5%的人口。 CCM被认为是遗传性和散发性的，其特征在于单簇或多簇 毛细血管样通道扩大，有单层内皮， 介入脑实质。脑内皮细胞有特殊的变化 屏障成分，最终导致血管通透性过高，红细胞外渗， 细胞和神经炎症反应。虽然在这方面取得了重大进展， 定义涉及遗传性CCM 3形式的基因突变，内部和 造成血管损伤的细胞间致病机制仍然主要是 未知脑内皮细胞表型的一个显著变化是细胞极性缺陷 这会影响细胞对环境刺激的反应，并可能使血管 损伤这项拟议的研究旨在阐明参与的关键分子事件， CCM 3条件下顶基极性的调节。它将突出显示 CCM 3和细胞极性复合物Par 3/Par 6/aPKC，通过我们的筛选分析鉴定 脑内皮细胞中CCM 3功能的丧失会严重影响其功能。具体 将评估大脑顶基底极性的结构和功能变化， 在CCM 3和CCM 3病变的修饰表达条件下的内皮细胞。 总的来说，这些研究将提供与泄漏的潜在原因有关的信息 和出血，为维持脑功能提供了新的见解。 内皮屏障也与多种疾病状态相关，希望， 阐明新的治疗策略，以恢复血管通透性。