Developmental Basis of Aneurysm in Marfan Syndrome and Therapeutic Implication

马凡氏综合征（MFS）是一种常见的疾病引起的基因突变编码的基质蛋白β 1。我们先前的工作已经表明，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TGF β家族生长因子的过度激活和信号传导引起的，并且可以通过小鼠模型中的TGF β阻断来减弱。流行的观点是，MFS表现出“正常”细胞的异常行为，这是由于细胞外环境的改变。我们现在提出的证据表明，成年MFS小鼠的主动脉壁内的“异常”细胞在早期发育过程中经历了一个TGF β依赖的身份和性格的永久性转变，由于一个过程称为内皮细胞间质转化（EnMT）。转化后，所得肌成纤维细胞表现出许多有害行为，包括高TGF β信号传导、血管紧张素II（AngII）依赖性纤维化和基质降解酶的高表达。在这项工作中要测试的主要假设是，EnMT衍生的细胞驱动疾病的进展，EnMT继续填充升主动脉在出生后的生活在疾病状态。使用小鼠模型，我们将确定驱动EnMT的途径，在主动脉中的EnMT-1缺陷小鼠，并将纯化EnMT衍生的细胞，允许识别他们的有害行为和探索策略，以驯服他们。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，这表明有可能快速转化为MFS患者。我们目前的数据表明，在MFS中明显获得迟发型表型的易感性中，细胞识别的发育强加的固定改变，这种范式代表了一种新的思考遗传易感性的方式，有助于阐明治疗的局限性和机会，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 TGF beta 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 alterations 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 transition in identity and character during early development due to a process termed endothelial-to-mesenchymal transition (EnMT). After transition, resulting 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 exploration 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 nonproductive 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 translation to people with MFS. Our current data suggest a developmentally-imposed fixed alteration in cellular identify in the prediposition for apparently acquired late-onset phenotypes in MFS, This paradigm represents a novel way of thinking about genetic predisposition, aids in the elucidation of therapeutic limitations and opportunities, and will likely prove relevant to other conditions.