Zonule Assembly and Ectopia Lentis

小带组装和异位晶状体

• 批准号: 8435502
• 负责人: SUNEEL S APTE
• 金额: $ 29.56万
• 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/8435502
• 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）：镜头在视路和适应性中的中心位置，依赖于Zinn的Zonule，Zinn是一种纤维纤维结构，该结构以Fibrillin-1为主要成分。 len骨的脱位，晶状体的脱位，是Marfan综合征（MFS）的主要表现，这是一种由Weill-Marchesani综合征的主要遗传疾病（由FBN1，ADAMTS10，ADAMTS10和ADAMTS17突变引起的）以及由ADAPIA LENTIS引起的（由FBN1，ADAMTS10和ADAMTS17突变引起的）（由fbn1，ADAMTS10引起），以及由Adam lentis（由Adam lentis）（由FBN1引起）。这些遗传发现强烈暗示了这些ADAMT（具有血小板蛋白类型1重复蛋白的脱整链蛋白样和金属蛋白酶）之间的功能联系。该提议的基本假设是ADAMTSL4，ADAMTS10和ADAMTS17对于Zinn Zonule的微纤维组件是Zinn Zonule的微纤维组件，因为该结构组织并桥梁固定睫状体和镜头。在此提案中，专注于ADAMTS17和ADAMTSL4，我们将使用表面等离子体共振进行分子间相互作用分析，以研究其与Fibrillin-1的单个分子间相互作用。我们将通过培养细胞在原纤维蛋白微纤维形成期间进行功能研究，并确定ADAMTSL4，Fibrillin-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合作起作用以促进Zonule的组装，并研究这些基因在Zonule发育过程中表达的空间和时间关系。这种实验策略将揭示Adamtsl4和Adamts17与Fibrillin-1和Adamts10的生化和功能关系。它将提供对卵形形成的机械理解和lentis的异端。目前尚无针对外胚层的特定治疗方法。通过这项工作获得的基本知识可以通过识别介导Zonule组装和稳定性的关键因素和机制来设计新型的Ectopia Lentis的治疗方法。