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（由申请人提供）：脑海绵状血管畸形（CCM）是一种常见的血管异常，易导致卒中和其他神经系统后遗症的终生风险。病变以散发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。Awad和Marchuk实验室对手术切除的CCM病变进行的分子遗传学分析揭示了血管腔内皮细胞中的二次打击体细胞CCM基因突变，表明CCM发病机制的二次打击突变机制。利用这些知识，我们已经开发出了强大的CCM动物模型，重现了人类病变的组织学，分子特征和超微结构。虽然我们现在可以描述病变发病机制的主要阶段，但调节这些阶段进展的潜在分子开关仍然未知。在平行的工作中，Ginsberg和其他实验室已经表明CCM基因功能的丧失损害了内皮细胞连接，部分由RhoA/ROCK活性调节。然而，Ginsberg、Kahn和其他实验室已经表明，CCM功能的丧失改变了其他主要的信号传导途径，如Notch、Wnt/β-连环蛋白、FOXO 1和KFL 2/MEKK 2信号传导。RhoA/ROCK活性在CCM发病机制中的中心地位及其最佳治疗靶点仍然未知。我们对P01提出的中心假设是CCM蛋白的丢失通过多种异常信号通路促进病变形成，其中一些是RhoA/ROCK独立的。我们进一步提出，不同的信号传导和遗传畸变调节病变发展和成熟的不同阶段。我们建议分析病变发展过程中的分子遗传事件，并在体内和体外研究相关信号。我们的小鼠模型使我们能够研究这些途径在CCM发病机制的不同阶段的体内作用，我们收集的手术切除的CCM使我们能够在临床相关的成熟人类病变中验证这些发现。对小鼠和人类病变的体外、体内和详细分析的连续体将帮助我们建立与病变发病机制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这种疾病的合理治疗策略。