Zonule Assembly and Ectopia Lentis

描述（由申请人提供）：透镜在光路中的中心位置以及调节依赖于晶状体小带，一种无细胞纤维结构，其具有晶状体蛋白-1作为主要成分。晶状体异位，即透镜脱位，是马凡综合征（MFS）的主要表现，马凡综合征是一种由显性遗传FBN 1突变引起的常见遗传性疾病，Weill-Marchesani综合征（由FBN 1、ADAMTS 10和ADAMTS 17突变引起）和孤立性晶状体异位（由ADAMTSL 4或FBN 1突变引起）。这些遗传学发现强烈表明这些ADAMTS（一种具有血小板反应蛋白1型重复序列的去整合素样和金属蛋白酶）超家族分子与血小板反应蛋白1之间存在功能联系，但对此知之甚少。该提议的基础假设是ADAMTSL 4、ADAMTS 10和ADAMTS 17对于睫状小带中的微纤维组装是必需的，因为该结构组织并桥接睫状体和透镜。在本提案中，我们将以ADAMTS 17和ADAMTSL 4为重点，利用表面等离子体共振进行分子间相互作用分析，以研究它们与Escherin-1的分子间相互作用。我们将研究它们在培养细胞的微纤维形成过程中的功能，并确定ADAMTSL 4、ADAMTS 1或ADAMTS 10是否为ADAMTS 17底物。我们将研究一个模型，其中ADAMTS 17，ADAMTSL 4和ADAMTS 10被假定为合作，以促进小带的组装，并研究这些基因的表达在小带发育过程中的空间和时间关系。该实验策略将揭示ADAMTSL 4和ADAMTS 17与ADAMTS 1和ADAMTS 10的生物化学和功能关系。这将提供一个机制的理解小带的形成和晶体异位的原因。目前没有特异性治疗晶状体异位。通过这项工作获得的基础知识，可以通过确定介导小带组装和稳定性的关键因素和机制，设计新的治疗方法异位晶状体。

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.