Novel therapeutic targets and/or prognostic markers in Marfan syndrome

马凡氏综合征（MFS）是一种先天性结缔组织疾病，是由细胞外微纤维的主要结构成分--β-淀粉样蛋白-1突变引起的。我们最初假设并随后证明，flbrillin-1突变损害了细胞外基质中潜伏TGF β复合物的螯合，对细胞性能产生有害后果。这一开创性的发现使人们认识到，TGF β阻断是一种有效的新策略，可以减轻MFS小鼠模型以及可能的人类患者的全身表现。我们现在提供的数据表明MAPKs和BMP是MFS小鼠模型中器官特异性异常的额外贡献者。这些令人兴奋的新发现与微纤维在几个TGF β超家族成员的细胞外储存中的新兴作用一致。它们也符合TGF β和BMP可以通过MAPK介导的途径发出信号以及MAPK可以影响Smad活性以响应环境应激和组织损伤的概念。 因此，我们假设flbrillin-1突变触发了一系列基质依赖性事件，这些事件破坏了个体组织中TGF β和BMP信号传导的生理平衡，并且p38 MAPK活性的不适当刺激可能导致细胞凋亡。（通过TGF β和/或应激反应信号）加剧了这种致病过程。因此，本项目的主要焦点是评估p38和BMP在进行性严重MFS小鼠模型中主动脉瘤和骨骼畸形发病机制中的潜在作用。具体地，我们提出： 目的1：探讨p38活性在Fbn 1突变小鼠主动脉瘤中的作用， 在非典型TGF β信号传导中有缺陷或用p38或Smad 2/3信号传导的抑制剂全身治疗。 目标二：使用Fbnl缺乏与TGF β或BMP II型受体的丧失或与BMP拮抗剂的过表达配对的小鼠，评价不平衡的TGF β和BMP信号传导在骨过度生长中的作用。 拟议的研究将补充并通过对ERK 1/2信号传导（项目1）、潜伏性TGF β激活剂（项目2）和结构异常细胞外基质（项目3）对主动脉瘤的贡献的平行研究提供信息。此外，核心B的独特试剂和成像服务将为工作提供关键支持。总的来说，我们的努力将揭示富含原纤维蛋白的微纤维在器官形成和功能中所起的生理作用的复杂性，此外还为MFS和结缔组织相关疾病的治疗干预提供了基于证据的机会。

Marfan syndrome (MFS) is a congenital disorder of the connective tissue that is caused by mutations in fibrillin-1, the major structural component of extracellular microfibrils. We have originally hypothesized and subsequently demonstrated that flbrillin-1 mutations impair the sequestration of latent TGFp complexes in the extracellular matrix with deleterious consequence to cell performance. This seminal discovery has led to the realization that TGFp blockade is a productive new strategy to mitigate systemic manifestations in mouse models of MFS and perhaps in human pafients. We now present data that implicate MAPKs and BMPs as addifional contributors to organ-specific abnormalifies in mouse models of MFS. These exciting new findings are consistent with the emerging role of microfibrils in the extracellular storage of several TGFp superfamily members. They are also in line with the notion that TGFp and BMPs can signal through MAPK-mediated pathways and that MAPKs can influence Smad activity in response to environmental stress and tissue injury. We therefore hypothesize that flbrillin-1 mutations trigger a series of matrix-dependent events that disrupt the physiological balance of TGFp and BMP signaling in individual tissues, and that improper stimulafion of p38 MAPK activity (through TGFp and/or stress-response signals) exacerbates this disease-causing process Accordingly, the main focus of the present project is to evaluate the potential role of p38 and BMPs in the pathogenesis of aortic aneurysm and skeletal deformities in mouse models of progressively severe MFS Specifically, we propose to: Aim 1: Interrogate the contribufion of p38 activity to aortic aneurysm in Fbn1 mutant mice that are also defective in non-canonical TGFp signaling or are systemically treated with inhibitors of p38 or Smad2/3 signaling. Aim 2: Evaluate the role of unbalanced TGFp and BMP signaling in bone overgrowth using mice in which Fbnl deficiency is paired with loss of TGFp or BMP type II receptors, or with over-expression of a BMP antagonist. The proposed studies will complement and be informed by parallel investigations on the contribution to aortic aneurysm of ERK1/2 signaling (Project 1), latent TGFp activators (Project 2) and a structurally abnormal extracellular matrix (Project 3). Additionally, the unique reagents and imaging services of Core B will provide critical support to the work. Collectively, our efforts will shed new light on the complexity of the physiological roles that fibrillin-rich microfibrils play in organ formafion and function, in addition to providing evidence-based opportunities for therapeutic intervention in MFS and related disorders of the connective tissue.