BIOMARKERS OF BRAIN PERMEABILITY IN HUMAN CEREBRAL CAVERNOUS MALFORMATIONS

描述(申请人提供)：脑海绵畸形(CCM)是一种常见的出血性血管畸形，表现为散发性和家族性常染色体显性形式，有三个已知的基因位点。它影响了100多万美国人，使他们有终身中风和癫痫的风险。目前还没有预防CCM病变发生或临床进展的治疗方法。我们的团队和其他人已经发现RhoA/ROCK信号与血管高通透性有关，是CCM发病的核心，我们开发了重现人类疾病的小鼠模型。我们正在进行的临床前研究表明，岩石活动是CCM疾病严重程度的生物标记物，其抑制是潜在的治疗方法。我们现在建议在人类CCM患者中进行一个探索性的开发项目，以转化来自小鼠模型的观察结果，这些观察结果将表明这种疾病的家族形式存在夸大的脑血管泄漏，而岩石活动是这种高通透性的潜在生物标记物。我们的团队已经确定了一大批人类CCM患者的特征，我们已经实施了使用磁共振动态对比增强定量灌注(DCEQP)Gd造影剂来量化人脑通透性的工具，并评估了患者外周血白细胞上ROCK活性的生物标志物。我们假设，三个CCM基因中的一个杂合子的家族性CCM疾病患者的脑血管通透性增加，CCM患者之间这种高通透性的差异反映了疾病严重程度的差异，并与外周血白细胞中的ROCK活性相关。这项研究将验证脑渗透性和血液生物测定作为CCM病中岩石活动的生物标志物的实用新工具。根据正在进行的临床前研究，我们的结果将为人类的概念提供进一步的证据。一种或两种技术可能被用于未来旨在预测和改变人类CCM疾病行为的研究中，并可能有助于在临床试验中校准岩石抑制疗法。它们将适用于其他脑部疾病，在这些疾病中，岩石介导的高渗透性已被假设为中心机制。

DESCRIPTION (provided by applicant): The cerebral cavernous malformation (CCM) is a common hemorrhagic vascular anomaly, presenting in sporadic and familial autosomal dominant forms, with three known gene loci. It affects more than a million Americans, predisposing them to a lifetime risk of stroke and epilepsy. There is currently no therapy to prevent the genesis or clinical progression of CCM lesions. Our group and others have implicated RhoA/ROCK signaling in vascular hyperpermeability central to CCM pathogenesis, and we developed murine models recapitulating the human disease. Our ongoing preclinical research has suggested ROCK activity as a biomarker of CCM disease severity, and its inhibition as potential therapy. We now propose an exploratory developmental project in human CCM patients, to translate observations from murine models that would suggest an exaggerated brain vascular leak in the familial form of the disease, and ROCK activity as a potential biomarker of this hyperpermeability. Our team has characterized a large cohort of human CCM patients, and we have implemented the tools to quantify human brain permeability using magnetic resonance dynamic contrast-enhanced quantitative perfusion (DCEQP) of gadolinium contrast agent, and to assess biomarkers of ROCK activity on peripheral blood leukocytes in patients. We hypothesize that vascular permeability is increased in the brain of patients with familial CCM disease who are heterozygous for one of the three CCM genes, that variances in this hyperpermeability among CCM patients reflect differences in disease severity, and correlate with ROCK activity in peripheral blood leukocytes. This research will validate practical novel tools of brain permeability and a blood bioassay as biomarkers of ROCK activity in CCM disease. In line with ongoing preclinical studies, our results will provide a further proof of concept in man. One or both techniques may be used in future research aimed at predicting and modifying CCM disease behavior in man and will likely help calibrate ROCK inhibition therapies in clinical trials. They will be applicable to other brain diseases where ROCK mediated hyperpermeability has been postulated as a central mechanism.