Role of Microfibrils in the Biology and Pathology of the Eye

描述（由申请人提供）：微原纤维蛋白（原纤维蛋白和潜伏性TGF β-结合蛋白）的突变是眼睛通常受到严重影响的综合征的基础。微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，微纤维调节转化生长因子β（TGF β）和骨形态发生蛋白（BMP）的生物利用度，这两类生长因子在眼睛发育和疾病中具有良好的记录作用。我们实验室的初步实验已经确定了眼睛中微纤维成分的分布和组织。这些研究还表明，在微纤维基因中携带靶向破坏的小鼠代表了用于研究微纤维在眼睛发育期间的信号作用的有希望的模型系统。基于我们的初步研究结果，我们将研究Fbn 2; 胚胎中表达最丰富的TGF β 1蛋白）在视裂闭合中的作用以及TGF β 1信号在这一过程中的作用。成年人的睫状小带几乎完全由微纤维组成。初步研究表明小带在透镜表面的附着点有助于确定透镜上皮的边缘，并在此过程中涉及BMP信号传导。将使用睫状体上皮非色素层中条件性缺失Rbn-1基因（Fbn 1;成人眼中主要Rbn亚型）的小鼠来检验该假设。最后，在人类中，LTBP 2（一种微纤维相关蛋白）的突变与早发性青光眼相关。因此，我们将测试Ltbp 2在 用肉眼观察并检查小鼠中Ltbp 2的缺失是否导致肿瘤表型。总之，这些实验将为微纤维在眼睛发育和疾病中的作用提供见解。由于微原纤维介导的信号通路易于药理学操作，因此我们的研究所产生的见解可能有助于指导这些目前难以治疗的疾病的有效治疗方案的开发。

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.