Investigating the molecular determinants of cerebral cavernous malformations downstream of MEKK3-KLF2/4 signaling

研究 MEKK3-KLF2/4 信号下游脑海绵状血管瘤的分子决定因素

• 批准号: 9907486
• 负责人: Courtney Hong
• 金额: $ 4.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907486
• 关键词: ADAMTS; ADAMTS1 gene; Biological Models; Biological Testing; Blood; Blood Vessels; Blood capillaries; Brain; Brain hemorrhage; CCM1 gene; Cardiac; Characteristics; Cleaved cell; Clinical; Complex; Cre-LoxP; DNA Sequence Alteration; Development; Diagnostic; Dilatation - action; Disease; Disease Pathway; Endothelial Cells; Endothelium; Environment; Event; Extracellular Matrix; Genetic; Genetic Transcription; Heart; Histologic; Knock-in Mouse; Lesion; Mediating; Mediator of activation protein; Medical; Metalloproteases; Modeling; Molecular; Molecular Cloning; Mus; Neonatal; Neuraxis; Neurologic; Neurologic Symptoms; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Progressive Disease; Proteins; Proteoglycan; Proteolysis; Recombinants; Resistance; Role; Seizures; Severities; Signal Pathway; Signal Transduction; Spinal Cord; Surface; System; TLR4 gene; Techniques; Testing; Tetracyclines; Therapeutic; Thinness; Transgenic Organisms; Venous; X-Ray Computed Tomography; base; behavior in vitro; brain endothelial cell; cerebral cavernous malformations; cerebrovascular; gene product; gut microbiome; improved; in vitro Model; in vivo; insight; loss of function mutation; mouse model; mutant; neurosurgery; neurovascular; novel; overexpression; postnatal; prevent; programs; response; rho; therapeutic target; transcription factor; vascular abnormality; venule; versican; white matter

Project Summary: Cerebral cavernous malformations (CCMs) are thin-walled, dilated vascular abnormalities that occur predominantly in the CNS and are a major cause of hemorrhagic strokes and seizures. Presently, there are no medical therapies for this progressive disease other than invasive neurosurgery. CCMs are caused by genetic mutations that result in the loss of a heterotrimeric adaptor complex required to negatively regulate MEKK3 signaling and the expression of the KLF2 and KLF4 transcription factors in brain endothelial cells. Recently, we have identified endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical upstream stimulators of MEKK3 signaling. However, the downstream effectors of this pathway relevant to disease pathogenesis have yet to be identified. In the neonatal mouse model of CCM disease, we have observed increased transcription of ADAMTS metalloproteases and ADAMTS-mediated processing of the ECM proteoglycan, versican, as early events in CCM development. This proposal will test the hypothesis that MEKK3-KLF2/4 signaling regulates the matrix environment, mediating versican processing by ADAMTS proteases, to promote CCM formation. Through the use of in vivo genetic mouse models and in vitro model systems, we will investigate the role of ADAMTS proteases (Aim 1) and their substrate, versican (Aim 2), as candidate downstream targets of this causal MEKK3 pathway. These studies are expected to yield new insights into the molecular molecules required to drive lesion genesis and findings may be used to direct the development of mechanism-based therapeutics for CCM disease.

项目概要： 脑海绵状畸形（CCM）是一种薄壁、扩张的血管异常， 主要在CNS中，并且是出血性中风和癫痫发作的主要原因。目前，没有 除了侵入性神经外科手术之外，这种进行性疾病的药物治疗。CCM是由遗传性 导致负调节MEKK 3所需的异源三聚体衔接子复合物丢失的突变 信号传导和脑内皮细胞中KLF 2和KLF 4转录因子的表达。最近我们 已经确定内皮Toll样受体4（TLR 4）和肠道微生物组是关键的上游刺激因子 MEKK 3信号然而，与疾病发病机制相关的该通路的下游效应物 还有待确认在CCM疾病的新生小鼠模型中，我们已经观察到增加的 ADAMTS金属蛋白酶的转录和ECM蛋白聚糖的ADAMTS介导的加工， versican，作为CCM发展的早期事件。该提案将检验MEKK 3-KLF 2/4 信号调节基质环境，介导ADAMTS蛋白酶的多功能蛋白聚糖加工，以促进 CCM编队。通过使用体内遗传小鼠模型和体外模型系统，我们将 研究ADAMTS蛋白酶（Aim 1）及其底物多功能蛋白聚糖（Aim 2）作为候选蛋白的作用 MEKK 3通路的下游靶点。预计这些研究将为人类的发展提供新的见解。 驱动损伤发生和发现所需的分子分子可用于指导 CCM疾病的基于机制的疗法。