Molecular Biology of Marfan Syndrome

描述（由申请人提供）： 翻译后摘要：马凡氏综合征（MFS）是一种常见的疾病所造成的基质蛋白的突变。MFS的许多表现，包括主动脉瘤和撕裂，是由过度的TGF β信号传导，特别是非经典ERK级联驱动的，并且可以在小鼠模型中被TGF β阻断剂减弱，包括FDA批准的药物氯沙坦。目前尚不清楚这些疗法是否适用于MFS患者，个体差异是否会限制对子集的反应，或者副作用是否会妨碍足够的剂量。我们 对β-胡萝卜素-1缺乏如何启动改变的TGF 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，例如患有MFS的孕妇，或者解释了在MFS中观察到的血管疾病的发作和严重程度的广泛家族内变异性。这些问题的答案将有直接的临床意义。目的1将建立在证明皮肤纤维化（硬皮病）的先天性表现是由β-内酰胺酶突变引起的基础上-β-内酰胺酶突变特异性地损害整合素与其RGD序列的结合。在β-淀粉样蛋白-1中携带RGD至RGE突变（导致整联蛋白结合的专性丧失）的小鼠显示与已知激活TGF β和ERK的整联蛋白亚型（avb 3）的表达增加相关的致密真皮纤维化，并且通过模拟β-淀粉样蛋白-1与其他整联蛋白（例如a5 b1）之间的相互作用的操作来保护其免受纤维化。我们的初步研究表明，RGE小鼠也发展主动脉瘤，提供了一个理想的系统来测试的假设，即基质细胞整合素-配体相互作用的损失是一个激动事件在MFS主动脉和测试整合素靶向治疗。目的2将利用我们最近的观察，钙通道阻滞剂（CCBs）迅速加速血管疾病在MFS小鼠。CCB给药和主动脉撕裂之间的紧密时间顺序将允许在应用先进的转录组和蛋白质组学分析方法时区分致病性和代偿性事件。目的3将探索MFS孕妇在妊娠结束时或产后立即发生主动脉撕裂的强烈倾向的机制和治疗方法-这是一个特别脆弱和研究不足的人群。催产素释放介导分娩和泌乳（通过激活ERK）与易感性时间之间的时间关联已经暗示催产素是心血管风险的潜在介导者。 这一假设将使用靶向遗传和药物试验进行测试。最后，目标4将定义和机械特性的第一个确定的主要修改基因座血管疾病的MFS已被映射到染色体6。这些研究有很强的潜力，揭示新的治疗目标和战略的MFS，也许更常见的介绍动脉瘤。

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.