Signaling Aberrations and Cerebral Cavernous Malformation Pathogenesis

信号畸变和脑海绵状血管瘤发病机制

基本信息

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
项目类别：
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

项目摘要

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）：脑海绵状血管瘤（CCM）是一种常见的血管异常，容易产生中风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。由于三个基因之一的突变，Awad 和 Marchuk 实验室对手术切除的 CCM 病变进行了分子遗传学分析，发现了二次打击的体细胞 CCM。血管腔内皮细胞的基因突变，表明 CCM 发病机制的二次突变机制，利用这些知识，我们开发了强大的 CCM 动物模型，概括了人类病变的组织学、分子特征和超微结构。虽然描述了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。Ginsberg 和其他实验室的并行工作表明，CCM 基因功能的丧失会损害。然而，Ginsberg、Kahn 和其他实验室已经表明，CCM 功能的丧失会改变其他主要信号传导途径，例如 Notch、Wnt/ß-catenin、FOXO1 和 KFL2/。 MEKK2 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。我们进一步提出，CCM 蛋白的丢失通过多种异常信号传导途径导致病变形成，其中一些信号传导途径与 RhoA/ROCK 无关。我们进一步提出，不同的信号传导和遗传异常调节病变发展和成熟的不同阶段。我们的小鼠模型使我们能够研究这些通路在病变发展过程中的遗传事件，并在体内和体外研究相关信号传导，并且我们收集的手术切除的 CCM 使我们能够研究这些通路在体内的作用。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、体内和详细分析将帮助我们创建与病变发病机制相关的异常信号网络的有序方案，并转化新的基本见解。为该疾病制定合理的治疗策略。