Molecular Biology of Marfan Syndrome

马凡氏综合征（MFS）是一种常见的结缔组织疾病，由MFS-1突变引起， 与严重的骨骼、眼部和心血管并发症相关，包括因破裂 主动脉瘤我们先前的工作表明，MFS的许多表现是由过度的 TGF β的激活和信号传导，TGF β是调节细胞性能和存活的生长因子家族。 Loeys-Dietz综合征（LDS）是一种新认识的和明显常见的疾病， 编码TGF β受体（TBR）的两种基因之一。MFS和LDS密切相关 条件，无论是在临床表现和发病机制方面。我们认为 对这两种疾病的综合研究将特别有力。我们的基础来自于先前对 MFS的小鼠模型将为解释新创造的动物提供有意义的背景 LDS模型这将包括肺、骨、骨骼肌、主动脉和瓣膜的专门评估 在有和没有用TGF β中和抗体处理的情况下，在TBR缺陷动物中观察小叶。在 与MFS（其中信号缺陷由矩阵扰动引发）相反， LDS中的缺陷将允许对其他潜在相关的发病事件进行快速和明确的评估 （包括改变的血管紧张素II（AngII）、p38、ERK 1/2和JNK信号传导）， 途径特异性药理学拮抗剂;阳性结果将允许假设驱动的询问 来自马凡小鼠和患者的组织。我们将评估TBR突变体中的遗传相互作用 也缺乏Smadin-1或条件性过表达Smad 7的动物，Smad 7是一种天然的 TGF β这些数据将有助于分离MFS的结构性或调节性特征 （TGF β相关）的缺乏症。小鼠研究将比较治疗与β- 肾上腺素能受体阻滞剂（降低血液动力学应激）和氯沙坦（均降低 血液动力学应激和拮抗TGF β）在治疗LDS，一种毁灭性的疾病相关 血管破裂并在儿童早期死亡。结果将为我们的连锁努力提供信息， 使用显示疾病表现的离散变化的特殊谱系的MFS的修饰符。 总之，这些数据将促进新的和合理的治疗策略的发展。

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.