Molecular Biology of Marfan Syndrome

描述(由申请人提供)： 摘要：马凡综合征(MFS)是一种由基质蛋白纤维蛋白-1突变引起的常见疾病。MFS的许多表现，包括主动脉瘤和撕裂，是由过度的TGFbeta信号，特别是非规范的ERK级联信号驱动的，并可以在小鼠模型中被TGFbeta阻滞剂缓解，包括FDA批准的药物氯沙坦。目前尚不清楚这种疗法是否对MFS患者有效，个体差异是否会限制对子集的反应，或者副作用是否会排除足够的剂量。我们的 对于纤维蛋白-1缺乏如何启动改变的转化生长因子β活性的理解仍然不完全。 关于最终导致组织衰竭的事件的知识也是如此，这些事件定义了特别脆弱的患者群体，如患有MFS的孕妇，或者解释了MFS中血管疾病的发病和严重程度的广泛家庭内部差异。这些问题的答案将具有直接的临床意义。目标1将建立在证明先天性皮肤纤维化(硬皮病)是由纤维蛋白突变引起的基础上，纤维蛋白突变专门损害整合素与其RGD序列的结合。在纤维蛋白-1中携带RGD到RGE突变(导致整合素结合的专性丧失)的小鼠表现出致密的皮肤纤维化I与一种已知激活TGFbeta和ERK的整合素亚型(Avb3)的表达增加有关，并通过模拟纤维蛋白-1和其他整合素(例如a5b1)之间的相互作用的操作来保护小鼠免受纤维化的影响。我们的初步研究表明，RGE小鼠也会发生主动脉瘤，这提供了一个理想的系统来检验以下假设：失去基质细胞整合素-配体相互作用是MFS主动脉中的激发事件，并测试整合素靶向治疗。目的2将利用我们最近观察到的钙通道阻滞剂(CCBS)迅速加速MFS小鼠血管疾病的观察。当应用先进的转录组和蛋白质组学分析方法时，CCB给药和主动脉撕裂之间的紧密时间序列将允许区分致病和代偿事件。目的3探讨MFS孕妇在妊娠末期或产后即刻有较强的主动脉撕裂倾向的机制和治疗方法。催产素的释放以调节分娩和哺乳(通过激活ERK)与易感时间之间的时间关联暗示了催产素是心血管风险的潜在介体。这一假设将通过有针对性的基因和药物试验来验证。最后，Aim 4将定义MFS中第一个已被定位到6号染色体的血管疾病的主要修饰基因，并对其进行机械表征。这些研究具有很强的潜力，可以揭示MFS的新治疗靶点和策略，也许还有更常见的动脉瘤表现。

DESCRIPTION (provided by applicant): Abstract: Marfan syndrome (MFS) is a common disorder caused by mutations in the matrix protein fibrillin-1. Many manifestations of MFS, including aortic aneurysm and tear, are driven by excessive TGFbeta signaling, particularly the noncanonical ERK cascade, and can be attenuated by TGFbeta blocking agents in mouse models, including the FDA-approved drug losartan. It is not known if such therapies will work in people with MFS, whether individual variation will limit response to a subset, or if side effects will preclude sufficient dosing. Our understanding of how fibrillin-1 deficiency initiates altered TGFbeta activity remains incomplete, as does knowledge regarding events that culminate in tissue failure, that define particularly vulnerable patient populations such as pregnant woman with MFS or that account for the wide intrafamilial variability in the onset and severity of vascular disease seen in MFS. Answers to these questions will have direct clinical implications. Aim 1 will build upon the demonstration that a congenital presentation of skin fibrosis (scleroderma) is caused by mutations in fibrillin- that specifically impair integrin binding to its RGD sequence. Mice harboring a RGD to RGE mutation in fibrillin-1 (causing an obligate loss of integrin binding) show dense dermal fibrosis i association with increased expression of an integrin subtype (avb3) known to activate TGFbeta and ERK, and are protected from fibrosis by manipulations that mimic the interaction between fibrillin-1 and other integrins (e.g. a5b1). Our preliminary studies show that RGE mice also develop aortic aneurysm, providing an ideal system to test the hypothesis that loss of matricellular integrin-ligand interaction is an inciting event in the MFS aorta and to test integrn-targeted therapies. Aim 2 will exploit our recent observation that calcium channel blockers (CCBs) rapidly accelerate vascular disease in MFS mice. The tight temporal sequence between CCB administration and aortic tear will allow discrimination between pathogenic and compensatory events when advanced transcriptome and proteomics profiling methods are applied. Aim 3 will explore mechanism and therapy for the strong predisposition for aortic tear at the end of pregnancy or in the immediate postnatal period in pregnant women with MFS - a particularly vulnerable and understudied population. The temporal association between release of oxytocin to mediate delivery and lactation (via activation of ERK) and the timing of predisposition has implicated oxytocin as a potential mediator of cardiovascular risk. This hypothesis will be tested using both targeted genetic and drug trials. Finally, Aim 4 will define and mechanistically characterize the first identified major modifying locus for vascular disease in MFS that has been mapped to chromosome 6. These studies have the strong potential to unveil novel therapeutic targets and strategies for MFS and perhaps more common presentations of aneurysm.