Zonule Assembly and Ectopia Lentis

描述（由申请人提供）：晶状体在光路中的中心位置以及调节依赖于Zinn的带状，Zinn是一种脱细胞纤维结构，其主要成分是纤原蛋白-1。晶状体异位，即晶状体脱位，是马凡综合征（MFS）、weil - marchesani综合征（由FBN1、ADAMTS10和ADAMTS17突变引起）和孤立性晶状体异位（由ADAMTSL4或FBN1突变引起）的主要表现。马凡综合征是一种常见的遗传性疾病，主要由FBN1突变引起。这些遗传发现强烈表明，这些ADAMTS（一种具有凝血蛋白1型重复的分离整合素样和金属蛋白酶）超家族分子与纤原蛋白1之间存在功能联系，对此知之甚少。该提议的假设是ADAMTSL4， ADAMTS10和ADAMTS17对于Zinn带中的微纤维组装是必不可少的，因为该结构组织和连接睫状体和晶状体。在本研究中，我们将以ADAMTS17和ADAMTSL4为研究对象，利用表面等离子体共振进行分子间相互作用分析，研究它们与fibrin -1的分子间相互作用。我们将研究它们在培养细胞形成原纤维微纤维过程中的功能，并确定ADAMTSL4、fibrin -1或ADAMTS10是否为ADAMTS17底物。我们将研究ADAMTS17、ADAMTSL4和ADAMTS10协同工作以促进区域规则组装的模型，并研究这些基因在区域规则发育过程中的表达时空关系。该实验策略将揭示ADAMTSL4和ADAMTS17与纤原蛋白1和ADAMTS10的生化和功能关系。它将提供一个机制的理解带状的形成和原因的异位晶状体。目前还没有针对异位晶状体的特殊治疗方法。通过这项工作获得的基础知识可以通过确定调节区组装和稳定性的关键因素和机制来设计新的治疗方法。

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.