Modifiers of disease Severity and Progression in Cerebral Cavernous Malformation

脑海绵状血管畸形（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CCM 1型（fCCM 1）是一种由KRIT 1基因突变引起的常染色体显性遗传疾病，其典型特征是MRI上的多发性病变，随着时间的推移，病变的数量和大小都会增加。患者存在明显的疾病负担差异，即使在相同基因突变、家族或年龄的携带者中也是如此。目前只有神经外科选项可供患者使用，尽管CCM动物模型的最新数据显示靶向RhoA（他汀类药物和法舒地尔）的药物在稳定内皮连接和减少血管渗漏方面具有良好的益处。在这个项目中，我们将利用我们在过去5年中的大量努力来招募，表型，并确定具有相同创始人突变（Q455 X）的fCCM 1患者中CCM疾病严重程度的修饰符，称为常见西班牙裔突变（CHM）。我们的长期目标是确定疾病严重程度的生物标志物，这可以帮助识别出血高危患者，这些患者将从药物治疗中获益最多，并为未来的临床治疗试验奠定基础。 在下一个资助期内，我们将继续对300例CCM 1-CHM病例进行纵向随访，以确定结果并更好地了解疾病的自然史，基于我们现有的全基因组关联数据来研究炎症在CCM中的作用，并扩大我们对临床试验生物标志物开发的关注，包括基因表达和神经影像学生物标志物。我们将招募一个由CHM和其他CCM 1基因突变引起的300例fCCM 1病例的复制队列，以评估CCM 1-CHM队列中发现的普遍性，并收集新的数据用于随访研究（包括血浆和血清样本，以及手术切除的组织标本）。我们提出以下目标：目标1：纵向表征CCM 1-CHM患者的表型表达和自然史。目的2：研究炎症在CCM 1疾病进展中的作用。目的3：开发预测疾病严重程度和进展的生物标志物，用于CCM的药物治疗。

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.