Zonule Assembly and Ectopia Lentis

小带组装和异位晶状体

• 批准号: 8625306
• 负责人: SUNEEL S APTE
• 金额: $ 30.49万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625306
• 关键词: ADAMTS; Address; Adult; Affect; Anterior; Binding; Binding Sites; Biochemical; Biological Assay; Cell Culture Techniques; Cells; Ciliary Body; Ciliary Muscle; Cleaved cell; Clinical; Complex; Crystalline Lens; Cultured Cells; Deposition; Development; Disease; Dislocations; Ectopia Lentis; Extracellular Matrix; Eye; FBN1; Fiber; Fibrillin Microfibrils; Gene Expression; Genetic; Goals; Hereditary Disease; Human; In Vitro; Individual; Inherited; Knowledge; Lens dislocation; Light; Link; Maintenance; Marfan Syndrome; Mediating; Messenger RNA; Metalloproteases; Microfibrils; Modeling; Mus; Muscle Contraction; Mutation; Natural regeneration; Optics; Outcome; Patients; Peptide Hydrolases; Positioning Attribute; Proteins; Recombinants; Role; Staging; Structure; Surface Plasmon Resonance; Syndrome; System; Testing; Tissues; Work; cell assembly; design; improved; intermolecular interaction; lens; member; novel therapeutic intervention; public health relevance

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.

描述（由申请人提供）：晶状体在视路中的中心位置以及调节依赖于Zinn小带，Zinn是一种无细胞纤维结构，其主要成分是fibrillin-1。晶状体异位（晶状体脱位）是马凡综合征 (MFS)（一种由显性遗传 FBN1 突变引起的常见遗传性疾病）、Weill-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。这些遗传发现强烈表明这些 ADAMTS（一种具有血小板反应蛋白 1 型重复序列的类分化素和金属蛋白酶）超家族分子与原纤维蛋白-1 之间存在功能联系，但对此我们知之甚少。该提议的假设是，ADAMTSL4、ADAMTS10 和 ADAMTS17 对于 Zinn 小带中微纤维的组装至关重要，因为该结构组织并桥接睫状体和晶状体。在本提案中，我们将重点关注 ADAMTS17 和 ADAMTSL4，利用表面等离子共振进行分子间相互作用分析，以研究它们各自与 fibrillin-1 的分子间相互作用。我们将研究它们在培养细胞原纤维蛋白微原纤维形成过程中的功能，并确定 ADAMTSL4、原纤维蛋白-1 或 ADAMTS10 是否是 ADAMTS17 底物。我们将研究一个模型，其中假定 ADAMTS17、ADAMTSL4 和 ADAMTS10 协同工作以促进小带的组装，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。该实验策略将揭示 ADAMTSL4 和 ADAMTS17 与 fibrillin-1 和 ADAMTS10 的生化和功能关系。它将提供对晶状体小带形成和晶状体异位原因的机制理解。目前晶状体异位没有具体的治疗方法。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来设计异位晶状体的新治疗方法。