Signaling Aberrations and Cerebral Cavernous Malformation Pathogenesis

信号传导异常与脑海绵状血管畸形发病机制。在该项目的第一个周期中，我们的合作小组已经取得了关于CCM发病机制的重大发现。在这次更新中，我们将继续这些发现，以科学为基础的治疗。来自我们项目中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缺陷内皮细胞毒害病变周围环境，以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，包括小鼠和人类病变中的单细胞基因组和转录组学分析以及小鼠模型中的机制研究。我们还发现，鼠和人CCM内的内皮细胞表达显著增加水平的血栓调节蛋白和内皮蛋白C受体，其导致内源性抗凝蛋白C的活化。这一发现为病变出血提供了一个新的靶点，这是与CCM相关的最具临床意义的表型。重要的是，为了使这些和其他研究，我们已经产生了新的，更强大的CCM小鼠模型，表现出快速病变生长和病变出血。我们还发现了一种与CCM生长有关的意想不到的新型信号传导异常-PI 3激酶的激活-这是现有药物和其他正在开发的药物的靶点。我们将研究PI 3激酶在CCM病变生长中的作用及其作为潜在治疗的抑制。同时，我们将寻找其他基因中的体细胞突变，这些突变可能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的成功，我们的更新旨在从发现到机制，然后再到CCM疾病的治疗研究。

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.