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.
The outcomes of the proposed work will result in an improved understanding of zonule formation and ectopia lentis mechanisms. The zonule is important because it centers the ocular lens in the path of light, and transmits ciliary muscle contraction to enable accommodation. Ectopia lentis occurs in 60% of patients with the Marfan syndrome, a common genetic disorder affecting the tissue microfibrils, which constitute the zonule. There is currently no specific treatment for ectopia lentis or for regeneration of the zonule. 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.
|Hubmacher, Dirk; Schneider, Michael; Berardinelli, Steven J et al. (2017) Unusual life cycle and impact on microfibril assembly of ADAMTS17, a secreted metalloprotease mutated in genetic eye disease. Sci Rep 7:41871|
|Hubmacher, Dirk; Wang, Lauren W; Mecham, Robert P et al. (2015) Adamtsl2 deletion results in bronchial fibrillin microfibril accumulation and bronchial epithelial dysplasia--a novel mouse model providing insights into geleophysic dysplasia. Dis Model Mech 8:487-99|
|Apte, Suneel S; Parks, William C (2015) Metalloproteinases: A parade of functions in matrix biology and an outlook for the future. Matrix Biol 44-46:1-6|
|Collin, Gayle B; Hubmacher, Dirk; Charette, Jeremy R et al. (2015) Disruption of murine Adamtsl4 results in zonular fiber detachment from the lens and in retinal pigment epithelium dedifferentiation. Hum Mol Genet 24:6958-74|
|Hubmacher, Dirk; Apte, Suneel S (2015) ADAMTS proteins as modulators of microfibril formation and function. Matrix Biol 47:34-43|
|Hubmacher, Dirk; Reinhardt, Dieter P; Plesec, Thomas et al. (2014) Human eye development is characterized by coordinated expression of fibrillin isoforms. Invest Ophthalmol Vis Sci 55:7934-44|
|Schlage, Pascal; Egli, Fabian E; Nanni, Paolo et al. (2014) Time-resolved analysis of the matrix metalloproteinase 10 substrate degradome. Mol Cell Proteomics 13:580-93|
|Beene, Lauren C; Wang, Lauren W; Hubmacher, Dirk et al. (2013) Nonselective assembly of fibrillin 1 and fibrillin 2 in the rodent ocular zonule and in cultured cells: implications for Marfan syndrome. Invest Ophthalmol Vis Sci 54:8337-44|
|Hubmacher, Dirk; Apte, Suneel S (2013) The biology of the extracellular matrix: novel insights. Curr Opin Rheumatol 25:65-70|
|Gabriel, Luis A R; Wang, Lauren W; Bader, Hannah et al. (2012) ADAMTSL4, a secreted glycoprotein widely distributed in the eye, binds fibrillin-1 microfibrils and accelerates microfibril biogenesis. Invest Ophthalmol Vis Sci 53:461-9|
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