Molecular Biology of Marfan Syndrome

马凡综合征(MFS)是一种常见的结缔组织疾病，由纤维蛋白-1突变引起，即 与严重的骨骼、眼部和心血管并发症有关，包括因破裂而死亡 主动脉瘤。我们先前的工作表明，MFS的许多表现是由过度 转化生长因子β是一类调节细胞性能和存活的生长因子家族，它激活并传递信号。 Loeys-Dietz综合征(LDS)是一种新发现的常见疾病，由基因突变引起。 编码转化生长因子β受体(TbR)的两个基因之一。MFS和LDS是密切相关的 在临床表现和致病机制方面。我们相信， 对这两种疾病的综合研究将特别强大。我们的基础来自于先前对 MFS的小鼠模型将提供一个有意义的上下文，在其中解释新创建的动物 LDS的模型。这将包括对肺、骨、骨骼肌、主动脉和瓣膜的专门评估。 TBR缺陷动物的小叶，经和不经转化生长因子β中和抗体处理。在……里面 与MFS(其中信号缺陷是由矩阵扰动引发的)不同，MFS的细胞自治性质 LDS中的缺陷将允许快速和明确地评估其他潜在相关的致病事件 (包括改变的血管紧张素II(Ang11)、p38、ERK1/2和JNK信号) 通路特定的药理拮抗剂；阳性结果将允许假说驱动的询问 来自马凡鼠和病人的组织。我们将评估TBR突变体的遗传交互作用 同样缺乏纤维蛋白-1或有条件地过度表达Smad7的动物，Smad7是一种天然的 TGFBeta。这些数据将有助于区分MFS的结构特征或监管特征 (转化生长因子β相关)纤维蛋白-1缺乏。小鼠的研究将比较贝塔试验的治疗效果。 肾上腺素能受体阻滞剂(降低血流动力学压力)与氯沙坦(两者均降低 血流动力学应激和拮抗转化生长因子β)治疗腰椎管狭窄症 在儿童早期就有血管破裂和死亡。结果将为我们识别基因的连锁努力提供信息 MFS的修饰者使用特殊的家系，在疾病表现中显示离散的变异。 综上所述，这些数据将有助于开发新的合理的治疗策略。

Marfan syndrome (MFS) is a common connective tissue disorder, caused by fibrillin-1 mutations, that is associated with severe skeletal, ocular, and cardiovascular complications including death due to ruptured aortic aneurysms. Our prior work has shown that many manifestations of MFS are caused byexcessive activation of and signaling by TGFbeta, a family of growth factors that regulate cell performance and survival. Loeys-Dietz syndrome (LDS) is a newly recognized and apparently common disorder caused by mutations in either of the two genes that encode the TGFbeta receptor (TBR). MFS and LDS are intimately related conditions, both in terms of clinical manifestations and pathogenetic mechanisms. We believe that the integrated study of both disorders will be particularly powerful. Our foundations derived from prior study of mouse models of MFS will provide a meaningful context within which to interpret newly created animal models of LDS. This will include a dedicated assessment of the lung, bone, skeletal muscle, aorta, and valve leaflets in TBR-deficient animals, both with and without treatment with TGFbeta neutralizing antibody. In contrast to MFS (where signaling defects are initiated by matrix perturbations), the cell-autonomous nature of the defect in LDS will allow rapid and definitive evaluation of other potentially relevant pathogenetic events (including altered angiotensin II (Angll), p38, ERK1/2 and JNK signaling) using cell culture systems and pathway-specific pharmacologic antagonists; positive results will allow for hypothesis-driven interrogation of tissues derived from Marfan mice and patients. We will evaluate for genetic interactions in TBR mutant animals that are also deficient for fibrillin-1 or that conditionally overexpress Smad7, a natural inhibitor of TGFbeta. These data will help to segregate features of MFS that manifest either structural or regulatory (TGFbeta-related) deficiencies of fibrillin-1. Mouse studies will compare the efficacy of treatment with a beta- adrenergic receptor blocker (that lowers hemodynamic stress) with that for losartan (that both lowers hemodynamic stress and antagonizes TGFbeta) in the treatment of LDS, a devastating disorder associated with vessel rupture and death in early childhood. Results will inform our linkage effort to identify genetic modifiers of the MFS using exceptional pedigrees that show discrete variation in disease manifestations. Taken together, these data will facilitate the development of novel and rational therapeutic strategies.