Signaling Aberrations and Cerebral Cavernous Malformation Pathogenesis

信号畸变和脑海绵状血管瘤发病机制

• 批准号: 9503080
• 负责人: Douglas A. Marchuk
• 金额: $ 126.84万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9503080
• 关键词: Affect; American; Animal Model; Animals; Biological Markers; Blood Vessels; Blood capillaries; Brain; CCM1 gene; Cardiovascular system; Chicago; Collection; Combined Modality Therapy; DNA; Development; Disease; Endothelial Cells; Event; FOXO1A gene; Gene Activation; Gene Expression; Gene Mutation; Gene Proteins; Genes; Genetic; Genetic Engineering; Growth; Hemorrhage; Histology; Human; Impairment; In Vitro; Individual; Inherited; Intercellular Junctions; Knock-out; Knowledge; Laboratories; Laboratory Study; Lasers; Lesion; Lesion by Stage; MAPK7 gene; Methodology; Microdissection; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Mus; Mutation; Neurologic; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Phenotype; Proteins; Publications; RNA; Reporting; Resected; Role; Scheme; Seizures; Signal Pathway; Signal Transduction; Stroke; TP53 gene; Therapeutic; Tissue-Specific Gene Expression; Translating; Translations; Treatment Efficacy; Work; base; beta catenin; cerebral cavernous malformations; clinically relevant; gene function; genetic analysis; human tissue; in vivo; insight; lifetime risk; mouse model; neurovascular; notch protein; novel; novel therapeutics; postnatal; programs; public health relevance; small molecule inhibitor; stroke risk; targeted treatment; therapeutic target; transcriptome sequencing; treatment optimization

 DESCRIPTION (provided by applicant): The cerebral cavernous malformation (CCM) is a common vascular anomaly, predisposing to a lifetime risk of stroke and other neurologic sequelae. Lesions occur in either a sporadic form or in an autosomal- dominant inherited form, the latter due to mutation in one of three genes. Molecular genetic analyses of surgically resected CCM lesions by the Awad and Marchuk laboratories has uncovered second-hit somatic CCM gene mutations in endothelial cells lining the vascular caverns, suggesting a two-hit mutational mechanism of CCM pathogenesis. Using this knowledge, we have developed robust animal models of CCM recapitulating the histology, molecular signatures and ultrastructure of the human lesions. Although we can now describe the major stages of lesion pathogenesis, the underlying molecular switches that modulate the progression of these stages remain unknown. In parallel work, the Ginsberg and other laboratories have shown that loss of CCM gene function impairs endothelial cell junctions, in part regulated by RhoA/ROCK activity. Yet, the Ginsberg, Kahn, and other laboratories have shown that loss of CCM function alters other major signaling pathways such as Notch, Wnt/ß-catenin, FOXO1, and KFL2/MEKK2 signaling. The centrality of RhoA/ROCK activity in CCM pathogenesis, and hence its optimal therapeutic target(s), remain unknown. Our central hypothesis of this P01 proposal is that the loss of CCM proteins contributes to lesion formation via multiple aberrant signaling pathways, some of which are RhoA/ROCK-independent. We further propose that different signaling and genetic aberrations modulate distinct stages of lesion development and maturation. We propose to analyze molecular genetic events during lesion development, and investigate associated signaling in vivo and in vitro. Our murine models enable us to investigate the role of these pathways in vivo at the different stages of CCM pathogenesis, and our collection of surgically resected CCMs allows us to validate these findings in the clinically relevant mature human lesion. The continuum of in vitro, in vivo and detailed analysis of mouse and human lesions will help us create an ordered scheme of aberrant signaling networks in relation to lesion pathogenesis, and translate new fundamental insights into rational therapeutic strategies for this disease.

 描述（由适用提供）：脑海绵状畸形（CCM）是一种常见的血管异常，倾向于中风和其他神经系统后遗症的终身风险。病变以零星形式或常染色体显性遗传形式发生，后者是由于三个基因之一的突变而引起的。 AWAD和Marchuk实验室对手术切除的CCM病变的分子遗传分析发现，在血管洞穴的内皮细胞中发现了第二次命中的体细胞CCM基因突变，这表明CCM病原体的两次冲击突变机制。利用这些知识，我们开发了CCM的强大动物模型，该模型概括了人类病变的组织学，分子特征和超微结构。尽管我们现在可以描述病变发病机理的主要阶段，但调节这些阶段进展的基础分子开关仍然未知。在同行工作中，金斯伯格和其他实验室表明，CCM基因功能的丧失会损害内皮细胞连接，部分受Rhoa/Rock活性调节。然而，金斯伯格，卡恩和其他实验室表明，CCM函数的损失改变了其他主要信号通路，例如Notch，Wnt/ß-Catenin，FoxO1和Kfl2/Mekk2信号传导。 RhoA/岩石活性在CCM发病机理中的中心性，因此其最佳治疗靶标仍然未知。我们对该P01提案的中心假设是，CCM蛋白的丧失通过多个异常信号通路有助于病变形成，其中一些是与RhoA/Rock无关的。我们进一步建议，不同的信号传导和遗传畸变调节病变发育和成熟的不同阶段。我们建议在病变发育过程中分析分子遗传事件，并研究体内和体外的相关信号传导。我们的鼠模型使我们能够在CCM发病机理的不同阶段研究这些途径在体内的作用，并且我们的手术切除的CCM收集使我们能够在临床上相关的成熟人类病变中验证这些发现。体外，体内和人类病变的详细分析的连续性将有助于我们创建与病变发病机理相关的异常信号网络的有序方案，并将新的基本见解转化为该疾病的理性治疗策略。