Developmental Basis of Aneurysm in Marfan Syndrome and Therapeutic Implication

马凡氏综合征（MFS）是一种常见的疾病所造成的基因突变编码的基质蛋白 -1。我们的前期工作表明，MFS的许多表现，包括主动脉瘤、瓣膜 疾病，肺气肿和骨骼肌肌病，是由过度激活和信号传导， TGF β家族的生长因子，并可在小鼠模型中通过TGF β阻断而减弱。的 流行的观点是，MFS表现出“正常”细胞的异常行为，这是由于它们的细胞周期发生了改变。 细胞外环境我们现在提出成人MFS主动脉壁内“异常”细胞的证据 在早期阶段经历了TGF β依赖性的身份和性格永久转变的小鼠， 由于称为内皮-间充质转化（EnMT）的过程，在过渡之后， 再生肌成纤维细胞表现出许多有害的行为，包括高TGF β信号，血管紧张素II （AngII）依赖性纤维化和基质降解酶的高表达。主要的假设是 在这项工作中测试的是，EnMT衍生的细胞驱动疾病的进展，EnMT继续 在疾病状态下的出生后生活期间填充升主动脉。使用小鼠模型，我们将确定 驱动EnMT在EkB-1缺陷小鼠的主动脉中的途径，并将纯化EnMT衍生的细胞， 允许识别它们的有害行为并探索驯服它们的策略。目前我们 可以设想至少9种不同的治疗剂，理论上可以预防正在进行的EnMT和/或 调节治疗开始时主动脉壁内肌成纤维细胞的非生产性能。这些将在遗传定义和验证的MFS小鼠模型中进行测试。 值得注意的是，这些药物中的一些已经在临床上用于其他适应症，这表明MFS患者有可能快速康复。我们目前的数据表明，在MFS中明显获得的晚发型表型的易感性中，细胞功能的发育强加的固定改变。这种范式代表了一种思考遗传易感性的新方式，有助于阐明治疗限制和机会，并可能证明与其他条件相关。

Marfan syndrome (MFS) is a common disorder caused by mutations in the gene encoding the matrix protein fibrillin-1. Our prior work has shown that many manifestations of MFS, including aortic aneurysm, valve disease, emphysema and skeletal muscle myopathy, are caused by excessive activation of and signaling by the TGFbeta family of growth factors and can be attenuated by TGFbeta blockade in mouse models. The prevailing view has been that MFS manifests abnormal behaviors of "normal" cells due to alterafions in their extracellular environment. We now present evidence for "abnormal" cells within the aortic wall of adult MFS mice that have undergone a TGFbeta-dependent permanent transifion in identity and character during early development due to a process termed endothelial-to-mesenchymal transifion (EnMT). After transifion, resulfing myofibroblasts exhibit many deleterious behaviors including high TGFbeta signaling, angiotensin II (Angll)-dependent fibrosis, and high expression of matrix-degrading enzymes. The major hypotheses to be tested in this work are that EnMT-derived cells drive progression of disease and that EnMT continues to populate the ascending aorta during postnatal life in disease states. Using mouse models, we will determine the pathways that drive EnMT in the aorta of fibrillin-1 deficient mice and will purify EnMT-derived cells, allowing identification of their deleterious behaviors and explorafion of strategies to tame them. Currently, we can envision at least 9 different therapeutic agents that will theoretically prevent ongoing EnMT and/or modulate the nonproducfive performance of myofibroblasts resident within the aortic wall at the time of initiation of treatment. These will be tested in genetically defined and validated mouse models of MFS. Remarkably, a number of these agents are already in clinical use for other indications, suggesting the potential for rapid translafion to people with MFS. Our current data suggest a developmentally-imposed fixed alterafion in cellular idenfity in the prediposition for apparently acquired late-onset phenotypes in MFS, This paradigm represents a novel way of thinking about genefic predisposifion, aids in the elucidation of therapeufic limitafions and opportunities, and will likely prove relevant to other condifions.