Developmental Basis of Aneurysm in Marfan Syndrome and Therapeutic Implication

马凡综合征 (MFS) 是一种由编码基质蛋白的基因突变引起的常见疾病 原纤维蛋白-1。我们之前的工作表明，MFS 的多种表现，包括主动脉瘤、瓣膜 肺气肿和骨骼肌肌病等疾病是由过度激活和信号传导引起的 TGFbeta 生长因子家族，并且可以通过小鼠模型中的 TGFbeta 阻断来减弱。的 普遍的观点是，MFS 表现出“正常”细胞的异常行为，这是由于其细胞结构的改变所致。 细胞外环境。我们现在提供成人 MFS 主动脉壁内“异常”细胞的证据 在早期阶段经历了TGFβ依赖性身份和性格永久转变的小鼠 由于内皮细胞向间质细胞转化（EnMT）的过程而产生的发育。转型后， 还原肌成纤维细胞表现出许多有害行为，包括高 TGFbeta 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。主要假设是 这项工作测试了 EnMT 衍生细胞驱动疾病进展，并且 EnMT 继续 在疾病状态下的出生后生活中填充升主动脉。使用小鼠模型，我们将确定 在 fibrillin-1 缺陷小鼠的主动脉中驱动 EnMT 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 在治疗开始时调节驻留在主动脉壁内的肌成纤维细胞的非生产性能。这些将在基因定义和验证的 MFS 小鼠模型中进行测试。 值得注意的是，其中许多药物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，在明显获得的 MFS 迟发表型的易感性中，细胞身份发生了发育性强加的固定改变。这种范式代表了一种思考遗传易感性的新方法，有助于阐明治疗限制和机会，并且可能会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.