The molecular pathogenesis of cerebral cavernous malformations

脑海绵状血管瘤的分子发病机制

基本信息

批准号：
9256639
负责人：
Alan Tien Tang
金额：
$ 4.86万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9256639
关键词：
ADAMTS Abscess Adaptor Signaling Protein Address Alleles Animals Basement membrane Binding Blood Vessels Brain CCM1 gene CD14 gene Cerebellum Clinical Complex Development Disease Disease model Doctor of Philosophy Embryo Endothelial Cells Endothelium Extracellular Matrix Extracellular Matrix Degradation FDA approved Fellowship GKLF protein General Population Genetic Genetic Polymorphism Genetic study Goals Heart Human Inflammatory Intra-abdominal Intraperitoneal Injections Lesion Lipopolysaccharides Mediating Medical Metalloproteases Mitogens Molecular Molecular Target Mus Neuraxis Neurologic Symptoms Pathogenesis Pathologic Pathway interactions Patients Peptide Hydrolases Pharmacology Phenotype Physicians Prevalence Proteins Proteoglycan Regulation Resected Resistance Role Scientist Severities Severity of illness Signal Pathway Signal Transduction Spinal Cord Stroke TLR4 gene Tamoxifen Testing Therapeutic Thinness Training cerebral cavernous malformations combinatorial experimental study gain of function genetic manipulation genome wide association study human disease inhibitor/antagonist loss of function mutation malformation mouse model nervous system disorder neurosurgery novel therapeutics overexpression postnatal pre-doctoral prevent receptor therapeutic target transcription factor versican white matter

项目摘要

This is a pre-doctoral fellowship application to support an MD/PhD candidate's training to become a physician-scientist dedicated to the study and treatment of neurological disorders. Cerebral cavernous malformations (CCMs) are thin-walled, dilated, vascular lesions that occur primarily in the brain and spinal cord, causing a variety of neurological symptoms and stroke. CCM disease is caused by loss of function mutations in three non-homologous adaptor proteins: CCM1 (KRIT1), CCM2 (OSM), and CCM3 (PDCD10), forming a heterotrimeric “CCM complex”. Evidence from mouse and patient studies strongly suggest that the CCM complex is specifically required in endothelial cells to prevent disease. This complex interacts with MEKK3 (MAP3K3) through direct binding between CCM2 and MEKK3. We have demonstrated, in a mouse model of CCM disease, that the CCM complex negatively regulates MEKK3 signaling in endothelial cells. In the disease state, disruption of the CCM complex results in gain of MEKK3 signaling and pathologic over-expression of KLF2 and KLF4 (KLF2/4) transcription factors. From genetic rescue experiments in mice and corroborating human disease studies, it is clear that this endothelial MEKK3—KLF2/4 pathway is required for the development of CCMs. The proposed studies will investigate downstream and upstream pathways of MEKK3—KLF2/4 signaling in the context of CCM disease with the overarching goal of identifying translational opportunities for the benefit of patients. In Aim 1, we will test the hypothesis that CCMs arise from the KLF2/4- driven, over-secretion of ADAMTS metalloproteases that undermine the extracellular matrix of the vasculature. This will be done using genetic rescue and sufficiency strategies in the CCM disease mouse model. Previous studies have shown Toll-like receptor 4 (TLR4) signaling to activate the MEKK3 pathway. Moreover, TLR4 polymorphisms are strongly associated with CCM disease severity in humans. In Aim 2, we will investigate the role of endothelial Toll-like receptor 4 (TLR4) signaling in CCM disease using pharmacologic and genetic manipulation of the CCM disease mouse model.

这是支持MD/PHD候选人的培训的博士前奖学金申请，以成为致力于研究和治疗神经系统疾病的身体科学家。脑海绵状畸形（CCM）是主要发生在大脑和脊髓中的薄壁，扩张，血管病变，导致各种神经系统症状和中风。 CCM疾病是由三种非理论衔接蛋白的功能突变丧失引起的：CCM1（KRIT1），CCM2（OSM）和CCM3（PDCD10），形成异三个型ccm复合物”。小鼠和患者研究的证据强烈表明，在内皮细胞中需要特异性CCM复合物来预防疾病。该复合物通过CCM2和MEKK3之间的直接绑定与MEKK3（MAP3K3）相互作用。我们已经在CCM疾病的小鼠模型中证明了CCM复合物对内皮细胞中的MEKK3信号进行负调节。在疾病状态下，CCM复合物的破坏会导致MEKK3信号传导和KLF2和KLF4（KLF2/4）转录因子的病理过表达的增加。从小鼠的遗传救援实验以及证实人类疾病研究的情况下，很明显，这种内皮MEKK3 -KLF2/4途径是CCM的发展所必需的。拟议的研究将在CCM疾病的背景下调查MEKK3 -KLF2/4信号的下游和上游途径，其总体目标是识别患者益处的翻译机会。在AIM 1中，我们将检验以下假设，即CCMS是由KLF2/4驱动的ADAMTS金属蛋白酶过度分泌的，从而破坏了脉管系统的细胞外基质。这将在CCM病小鼠模型中使用遗传救援和充足策略完成。先前的研究表明，Toll样受体4（TLR4）信号传导以激活MEKK3途径。此外，TLR4多态性与人类的CCM疾病严重程度密切相关。在AIM 2中，我们将使用CCM疾病小鼠模型的药理学和遗传操纵在CCM疾病中调查内皮收费样受体4（TLR4）信号的作用。