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: 10220142
• 负责人: Douglas A. Marchuk
• 金额: $ 131.07万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10220142
• 关键词: 1-Phosphatidylinositol 3-Kinase; ADAMTS; Acute; Affect; American; Animals; Anticoagulants; Blood; Blood Vessels; Blood capillaries; Brain; Cell Lineage; Cells; Chronic; Clinical Trials; Collection; Communities; Complex; Data; Development; Disease; Endothelial Cells; Endothelium; Environment; Event; Exhibits; Genes; Genetic Engineering; Genomics; Genotype; Goals; Growth; Hemorrhage; Histology; Human; Investigation; Investigational Therapies; Laboratories; Lead; Lesion; Lesion by Stage; Modeling; Molecular; Molecular Probes; Molecular Profiling; Mus; Mutate; Mutation; Neurologic; Operative Surgical Procedures; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Poison; Preparation; Process; Protein C; Role; Seizures; Signal Pathway; Signal Transduction; Somatic Mutation; Specimen; Stroke; TLR4 gene; Testing; Therapeutic Studies; Thrombomodulin; Tissues; Work; X-Ray Computed Tomography; activated protein C receptor; base; cell behavior; cerebral cavernous malformations; clinically significant; design; drug testing; follow-up; gain of function; genomic locus; gut microbiome; insight; lifetime risk; molecular marker; mouse model; mutant; new therapeutic target; novel; novel marker; overexpression; pre-clinical; programs; recruit; stroke risk; success; therapeutic target; tool; transcriptomics; versican

Signaling Aberrations and Cerebral Cavernous Malformations Pathogenesis. In the first cycle of this program project our collaborative group has made significant discoveries concerning CCM pathogenesis. In this renewal we will follow up these discoveries towards a scientifically based therapy. Recent data from multiple laboratories in our program converge on a model in which somatically mutated, CCM-deficient endothelial cells poison the peri-lesional environment to recruit non-deficient cells into the growing lesion. We will investigate the molecular and cellular basis for this non-cell autonomous pathological mechanism, including single-cell genomic and transcriptomic analyses in mouse and human lesions and mechanistic studies in mouse models. We have also discovered that endothelial cells within murine and human CCMs express markedly increased levels of thrombomodulin and endothelial protein C receptor which leads to activation of endogenous anti-coagulant protein C. This discovery provides a new target for lesional hemorrhage, the most clinically significant phenotype associated with CCM. Importantly, to enable these and other studies we have generated new, more robust CCM mouse models that exhibit both rapid lesion growth and lesional hemorrhage. We have also identified an unexpected and novel signaling aberration involved in CCM growth – activation of PI3 kinase – a target with existing drugs and with others under development. We will investigate the role of PI3 kinase in CCM lesion growth and its inhibition as a potential therapy. In parallel, we will search for somatic mutations in other genes that might enable repurposing of other existing drugs for CCM therapy. By capitalizing on our successes over the past four years, our renewal is designed to move from discovery, to mechanism, and then on to investigation of therapies for CCM disease.

信号畸变和脑海绵状畸形发病机理。在该计划项目的第一个周期中，我们的协作小组就CCM发病机理提出了重大发现。在这种续签中，我们将跟进这些发现，以进行基于科学的疗法。来自我们程序中多个实验室的最新数据汇聚在一个模型中，在该模型中，体面突变的CCM缺乏内皮细胞中毒了静脉内环境，将非缺陷细胞募集到生长的病变中。我们将研究这种非细胞自主病理机制的分子和细胞基础，包括小鼠和人病变中的单细胞基因组和转录组分析以及小鼠模型中的机械研究。我们还发现，鼠和人CCM中的内皮细胞显着提高了血小板调节蛋白和内皮蛋白C受体的水平，这会导致激活内源性抗凝蛋白C的激活C。这一发现为拟态出血提供了一个新的靶标，是与CCM相关的最重要的临床出血。重要的是，为了实现这些和其他研究，我们产生了新的，更强大的CCM小鼠模型，既表现出快速损伤生长又显示病变的出血。我们还确定了CCM增长涉及的意外和新颖的信号畸变 - PI3激酶的激活 - 一种具有现有药物以及正在开发的其他药物的靶标。我们将研究PI3激酶在CCM病变生长中的作用及其作为一种潜在疗法的抑制作用。同时，我们将在其他基因中搜索可以重新使用其他现有药物进行CCM治疗的基因突变。通过利用过去四年的成功，我们的续约旨在从发现，机制转变为CCM疾病疗法的调查。