Role of Microfibrils in the Biology and Pathology of the Eye

描述（由申请人提供）：微纤维蛋白（纤原蛋白和潜伏TGF¿-结合蛋白）突变是眼部典型且经常受到严重影响的综合征的基础。微原纤维是细胞外基质的关键受力元件，但最近的研究表明，它们也是生长因子信号传导的重要枢纽。具体来说，微原纤维调节转化生长因子β （TGF¿）和骨形态发生蛋白（BMPs）的生物利用度，这两类生长因子在眼睛发育和疾病中发挥着充分的作用。我们实验室的初步实验已经确定了微纤维成分在眼睛中的分布和组织。这些研究还表明，携带微原纤维基因靶向破坏的小鼠为研究微原纤维在眼睛发育过程中的信号作用提供了有希望的模型系统。基于我们的初步结果，我们将研究纤颤蛋白2 (Fbn2；

DESCRIPTION (provided by applicant): Mutations in microfibril proteins (fibrillins and latent- TGF¿-binding proteins) underlie syndromes in which the eye is typically, and often severely, affected. Microfibrils are key force-bearing elements of the extracellular matrix but recent studies have shown that they also serve as important hubs for growth factor signaling. Specifically, microfibrils regulate the bioavailability of both transforming growth factor beta (TGF¿) and bone morphogenetic proteins (BMPs), two classes of growth factors with well-documented roles in eye development and disease. Preliminary experiments from our laboratory have determined the distribution and organization of microfibril components in the eye. These studies also demonstrated that mice harboring targeted disruptions in microfibril genes represent promising model systems for studying the signaling role of microfibrils during eye development. Building on our preliminary results we will examine the role of fibrillin-2 (Fbn2; the most abundantly expressed fibrillin in the embryo) in closure of the optic fissure and the contribution of TGF¿ signaling to this process. The ciliary zonule of the adult eye is composed almost entirely of microfibrils. Preliminary studies suggest that the attachment point of the zonule on the lens surface helps to specify the edge of the lens epithelium and implicated BMP signaling in this process. This hypothesis will be tested using mice in which the fibrillin-1 gene (Fbn1; the major fibrillin isoform in the adult eye) is conditionally deleted in the non-pigmented layer of the ciliary epithelium. Finally, in humans, mutations in LTBP2, a microfibril-associated protein, are associated with early onset glaucoma. Therefore, we will test the role of Ltbp2 in the eye and examine whether deletion of Ltbp2 in mice leads to a glaucomatous phenotype. Together, the experiments will provide insights into the role of microfibrils during eye development and disease. Because the signaling pathways mediated by microfibrils are amenable to pharmacologic manipulation, insights arising from our studies may help guide the development of effective treatment regimens for these currently intractable conditions.