BIOMARKERS OF BRAIN PERMEABILITY IN HUMAN CEREBRAL CAVERNOUS MALFORMATIONS

描述（由申请人提供）：脑海绵状血管畸形（CCM）是一种常见的出血性血管异常，以散发性和家族性常染色体显性形式存在，具有三个已知的基因位点。它影响了100多万美国人，使他们一生都有患中风和癫痫的风险。目前尚无预防CCM病变发生或临床进展的治疗方法。我们的小组和其他人已经将RhoA/ROCK信号传导与CCM发病机制的血管通透性过高联系起来，并且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，ROCK活性是CCM疾病严重程度的生物标志物，其抑制作用是潜在的治疗方法。我们现在提出了一个探索性的发展项目，在人类CCM患者，翻译观察从小鼠模型，这将表明一个夸大的脑血管渗漏的家族形式的疾病，和ROCK活性作为一个潜在的生物标志物，这种高渗透性。我们的团队已经表征了一个大型的CCM患者队列，并且我们已经使用钆造影剂的磁共振动态对比增强定量灌注（DCEQP）来量化人脑渗透性，并评估患者外周血白细胞上ROCK活性的生物标志物。我们假设，家族性CCM疾病患者的脑血管通透性增加，这些患者是三个CCM基因之一的杂合子，CCM患者中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疾病中ROCK活性生物标志物的实用新工具。与正在进行的临床前研究一致，我们的结果将为人类提供进一步的概念验证。一种或两种技术可能用于未来的研究，旨在预测和改变人类CCM疾病行为，并可能有助于在临床试验中校准ROCK抑制疗法。他们将适用于其他脑疾病，其中ROCK介导的高渗透性已被假定为一个中央机制。

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.