Novel therapeutic targets and/or prognostic markers in Marfan syndrome

马凡综合征(MFS)是一种先天性结缔组织疾病，由细胞外微纤维的主要结构成分原纤维-1的突变引起。我们最初假设并随后证明，氟布林-1突变损害了潜在的TGFp复合体在细胞外基质中的隔离，从而对细胞性能造成有害后果。这一开创性的发现使人们认识到，阻断TGFp是一种有效的新策略，可以减轻MFS小鼠模型的全身症状，也许还可以减轻人类患者的全身症状。我们现在提供的数据表明，MAPK和BMP是MFS小鼠模型中器官特异性异常的附加贡献者。这些令人兴奋的新发现与微纤维在几个TGFp超家族成员的细胞外存储中的新角色是一致的。它们也与TGFp和BMPs可以通过MAPK介导的通路传递信号以及MAPK可以影响Smad的活性以响应环境应激和组织损伤的观点一致。 因此，我们假设flbrins-1突变触发了一系列基质依赖的事件，破坏了单个组织中TGFp和BMP信号的生理平衡，并且不适当地刺激p38MAPK活性(通过TGFp和/或应激反应信号)相应地加剧了这一致病过程。本项目的主要重点是评估p38和BMPs在进行性严重MFS小鼠模型主动脉瘤和骨骼畸形发病机制中的潜在作用。 目的1：探讨p38活性在Fbn1突变小鼠主动脉瘤发病中的作用 在非规范的TGFp信号转导方面存在缺陷，或者使用p38或Smad2/3信号转导的抑制剂进行系统治疗。 目的：在Fbn1缺乏伴TGFp或BMP II型受体缺失或BMP拮抗剂过度表达的小鼠模型中，评价TGFp和BMP信号失衡在骨过度生长中的作用。 建议的研究将补充ERK1/2信号(项目1)、潜在的TGFp激活物(项目2)和结构异常的细胞外基质(项目3)在主动脉瘤中的作用的平行研究。此外，Core B独特的试剂和成像服务将为这项工作提供关键支持。总而言之，我们的努力将对富含纤维蛋白的微纤维在器官形成和功能中扮演的复杂生理角色提供新的认识，并为MFS和相关结缔组织疾病的治疗干预提供循证机会。

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.