Zonule Assembly and Ectopia Lentis

描述(申请人提供)：晶状体在光路中的中心位置以及调节，依赖于Zinn的小带，Zinn是一种无细胞的纤维结构，其主要成分是纤维蛋白-1。晶状体脱位是马凡综合征(MFS)、Weill-Marchesani综合征(由FBN1、ADAMTS10和ADAMTS17突变引起)和孤立异位晶状体(由ADAMTSL4或FBN1突变引起)的主要表现。这些遗传学发现有力地表明了这些ADAMTS(具有凝血酶反应蛋白类型1重复的类去整合素和金属蛋白酶)超家族分子与纤维蛋白-1之间的功能联系，人们对此知之甚少。提出的假设是，ADAMTSL4、ADAMTS10和ADAMTS17是Zinn带中微纤维组装所必需的，因为这个结构组织和连接睫状体和晶状体。在本提案中，我们将以ADAMTS17和ADAMTSL4为研究对象，利用表面等离子体共振技术进行分子间相互作用分析，研究它们与纤维蛋白-1的分子间相互作用。我们将研究它们在培养细胞形成纤维蛋白微原纤维过程中的功能，并确定ADAMTSL4、纤维蛋白-1或ADAMTS10是否为ADAMTS17底物。我们将研究一个假设ADAMTS17、ADAMTSL4和ADAMTS10协同工作以促进小带组装的模型，并研究这些基因在小带发育过程中表达的空间和时间关系。这一实验策略将揭示ADAMTSL4和ADAMTS17与纤维蛋白-1和ADAMTS10的生化和功能关系。它将提供对晶状体小带形成和异位晶状体的原因的机制的理解。目前还没有针对异位晶状体的特效治疗方法。通过这项工作获得的基础知识可以通过识别调节晶状体小带组装和稳定性的关键因素和机制来设计新的异位晶状体治疗方法。

DESCRIPTION (provided by applicant): The central position of the lens in the optic path as well as accommodation, rely on the zonule of Zinn, an acellular fibrous structure, which has fibrillin-1 as a major component. Ectopia lentis, dislocation of the lens, is a major manifestation of the Marfan syndrome (MFS), a common genetic disorder caused by dominantly inherited FBN1 mutations, of Weill-Marchesani syndrome (caused by FBN1, ADAMTS10 and ADAMTS17 mutations), and isolated ectopia lentis (caused by ADAMTSL4 or FBN1 mutations). These genetic findings strongly suggest a functional link between these ADAMTS (A distintegrin-like and metalloprotease with thrombospondin type-1 repeat) superfamily molecules and fibrillin-1, about which little is known. The hypothesis underlying the proposal is that ADAMTSL4, ADAMTS10 and ADAMTS17 are esential for microfibril assembly in the zonule of Zinn as this structure organizes and bridges the ciliary body and lens. In this proposal, focusing on ADAMTS17 and ADAMTSL4, we will undertake intermolecular interaction analysis using surface plasmon resonance to investigate their individual intermolecular interactions of with fibrillin-1. We will investigate them functionally during fibrillin microfibril formation by cultured cells, and determine whether ADAMTSL4, fibrillin-1 or ADAMTS10 are ADAMTS17 substrates. We will investigate a model in which ADAMTS17, ADAMTSL4 and ADAMTS10 are postulated to work cooperatively to facilitate assembly of the zonule, and investigate the spatial and temporal relationships of the expression of these genes during zonule development. This experimental strategy will reveal the biochemical and functional relationships of ADAMTSL4 and ADAMTS17 with fibrillin-1 and ADAMTS10. It will provide a mechanistic understanding of zonule formation and the cause of ectopia lentis. There is currently no specific treatment for ectopia lentis. The fundamental knowledge obtained through this work may allow design of novel therapeutic approaches for ectopia lentis by identifying the critical factors and mechanisms that mediate zonule assembly and stability.