Signaling Aberrations and Cerebral Cavernous Malformation Pathogenesis

信号异常与脑海绵状血管瘤的发病机制。在这个项目的第一个周期中，我们的合作小组在CCM发病机制方面取得了重大发现。在这次更新中，我们将跟踪这些发现，以科学为基础的治疗。最近来自我们项目中多个实验室的数据集中在一个模型上，在这个模型中，体细胞突变、ccm缺陷的内皮细胞毒害病变周围的环境，以招募非缺陷细胞进入生长的病变。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的单细胞基因组学和转录组学分析以及小鼠模型的机制研究。我们还发现，小鼠和人CCM内的内皮细胞表达的血栓调节蛋白和内皮蛋白C受体水平显著升高，从而导致内源性抗凝血蛋白C的激活。这一发现为病变性出血提供了新的靶点，病变性出血是与CCM相关的最具临床意义的表型。重要的是，为了实现这些和其他研究，我们已经产生了新的、更健壮的CCM小鼠模型，这些模型既表现出快速的病变生长，也表现出病变出血。我们还发现了一个意想不到的和新的信号畸变，涉及CCM生长- PI3激酶的激活-现有药物和其他正在开发的药物的靶标。我们将研究PI3激酶在CCM病变生长中的作用及其抑制作为一种潜在的治疗方法。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。通过利用我们过去四年的成功，我们的更新旨在从发现，到机制，然后再到研究CCM疾病的治疗方法。

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.