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: 10417150
• 负责人: Douglas A. Marchuk
• 金额: $ 130.33万
• 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/10417150
• 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.

信号异常与脑海绵状血管畸形的发病机制。在这个计划项目的第一个周期中，我们的合作小组已经在CCM的发病机制方面取得了重大发现。在这次更新中，我们将跟进这些发现，以寻求一种基于科学的治疗方法。我们计划中来自多个实验室的最新数据集中在一个模型上，在该模型中，体细胞突变的CCM缺陷内皮细胞毒化周围环境，将非缺陷细胞招募到生长的病变中。我们将研究这种非细胞自主病理机制的分子和细胞基础，包括在小鼠和人类病变中的单细胞基因组和转录分析，以及在小鼠模型中的机制研究。我们还发现，小鼠和人CCM中的内皮细胞表达显著增加的血栓调节蛋白和内皮蛋白C受体，从而导致内源性抗凝蛋白C的激活。这一发现为临床上与CCM相关的最显著的表型--皮损出血提供了新的靶点。重要的是，为了使这些研究和其他研究成为可能，我们建立了新的、更健壮的CCM小鼠模型，这些模型既显示了病变的快速增长，又显示了皮损出血。我们还发现了与CCM生长有关的一种意想不到的新的信号异常-PI3激酶的激活-现有药物和其他正在开发的药物的靶点。我们将研究PI3激酶在CCM病变生长中的作用及其抑制作为一种潜在的治疗方法。与此同时，我们将在其他基因中寻找体细胞突变，这些基因可能会使其他现有药物重新用于CCM治疗。通过利用我们在过去四年中取得的成功，我们的更新旨在从发现到机制，然后转向CCM疾病的治疗方法的研究。