Modifiers of disease Severity and Progression in Cerebral Cavernous Malformation

脑海绵状血管瘤（CCM）是一种渗漏性血管病变，可引起出血性中风、癫痫发作和神经功能缺损。家族性CCM1型（fCCM1）是由KRIT1基因突变引起的常染色体显性疾病，其典型特征是MRI上出现多个病变，随着时间的推移，病变的数量和大小都在增加。即使在同一基因突变携带者、家庭或年龄之间，患者的疾病负担也存在显著差异。虽然最近CCM动物模型的数据显示，针对RhoA的药物（他汀类药物和法舒地尔）在稳定内皮连接和减少血管渗漏方面有很好的益处，但目前只有神经外科治疗可供患者选择。在这个项目中，我们将利用过去5年的大量努力，在具有相同的创始突变（Q455X）的fCCM1患者中招募、表型和鉴定CCM疾病严重程度的修饰因子，该突变被称为常见西班牙突变（CHM）。我们的长期目标是确定疾病严重程度的生物标志物，这可以帮助识别从药物治疗中获益最多的出血高危患者，并为未来的临床治疗试验奠定基础。

Cerebral Cavernous Malformations (CCM) are leaky vascular lesions that cause hemorrhagic strokes, seizures, and neurological deficits. Familial CCM type 1 (fCCM1) is an autosomal dominant disease caused by mutations in the KRIT1 gene, and is typically characterized by multiple lesions on MRI that increase in number and size over time. Patients present with marked variability of disease burden, even among carriers of the same gene mutation, family or age. Currently only neurosurgical options are available to patients, although recent data from CCM animal models show promising benefits of drugs that target RhoA (statins and fasudil) for stabilizing endothelial junctions and reducing vascular leakage. In this project, we will leverage our considerable efforts over the past 5 years to recruit, phenotype, and identify modifiers of CCM disease severity in fCCM1 patients with the same founder mutation (Q455X), known as the Common Hispanic Mutation (CHM). Our long-term goal is to identify biomarkers for disease severity, which could aid in identifying patients at high risk for hemorrhage who would benefit most from pharmacologic therapy, and sets the stage for future clinical treatment trials. In the next funding period, we will continue longitudinal follow-up of 300 CCM1-CHM cases to ascertain outcomes and better understand the natural history of the disease, build on our existing genome wide association data to investigate the role of inflammation in CCM, and expand our focus on biomarker development for clinical trials, including gene expression and neuroimaging biomarkers. We will recruit a replication cohort of 300 fCCM1 cases caused by CHM and other CCM1 gene mutations to assess generalizability of findings in the CCM1-CHM cohort, and collect new data for follow-up studies (including plasma and serum samples, and surgically resected tissue specimens). We propose the following aims: Aim 1: To longitudinally characterize the phenotypic expression and natural history of CCM1-CHM patients. Aim 2: To investigate the role of inflammation in CCM1 disease progression. Aim 3: To develop biomarkers predictive of disease severity and progression for medical treatment of CCM.