Developmental Basis of Aneurysm in Marfan Syndrome and Therapeutic Implication

马凡综合征(MFS)是一种常见的疾病，由编码基质蛋白的基因突变引起 纤维蛋白-1。我们先前的工作表明，MFS的许多表现，包括主动脉瘤、瓣膜 疾病，肺气肿和骨骼肌病，是由过度激活和信号传递引起的 TGFbeta是生长因子家族中的一种，在小鼠模型中可被TGFbeta阻断而减弱。这个 流行的观点认为，MFS表现出“正常”细胞的异常行为，这是由于其 细胞外环境。我们现在提出证据表明成人MFS的主动脉壁内存在“异常”细胞。 在早期经历了转化生长因子β依赖的永久性转变的小鼠的身份和特征 这是一种称为内皮细胞到间充质细胞转化(EnMT)的过程。在交接之后， 结果肌成纤维细胞表现出许多有害行为，包括高转化生长因子β信号、血管紧张素II (Ang11)依赖的纤维化，以及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来源的细胞推动了疾病的进展，并且EnMT继续 在出生后处于疾病状态的生命中填充升主动脉。使用老鼠模型，我们将确定 在纤维蛋白-1缺陷小鼠的主动脉中驱动EnMT的途径，并将纯化EnMT来源的细胞， 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 我可以设想至少9种不同的治疗药物，从理论上防止正在进行的EnMT和/或 调节治疗开始时驻留在主动脉壁内的肌成纤维细胞的非生成性表现。这些将在MFS的遗传定义和验证的小鼠模型中进行测试。 值得注意的是，其中一些药物已经在临床上用于其他适应症，这表明有可能对MFS患者进行快速转移。我们目前的数据表明，在MFS中，明显获得性迟发性表型的前置存在发育强加的细胞同一性的固定变化，这一范式代表了一种新的思考基因前置的方式，有助于阐明治疗的局限性和机会，并可能被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.