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(纤维蛋白和潜伏的转化生长因子结合蛋白)突变是眼睛受到典型且通常严重影响的综合征的基础。微纤维是细胞外基质的关键承力元件，但最近的研究表明，它们也是生长因子信号转导的重要枢纽。具体地说，微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的作用已得到充分证明。我们实验室的初步实验已经确定了眼内微纤维成分的分布和组织。这些研究还表明，携带有针对性的微原纤维基因中断的小鼠是研究微原纤维在眼睛发育过程中的信号作用的有前途的模型系统。在我们初步结果的基础上，我们将研究纤维蛋白-2(Fbn2； 在胚胎中表达最丰富的原纤维蛋白)在视裂闭合过程中以及转化生长因子β信号在这一过程中的作用。成人眼的睫状带几乎全部由微纤维组成。初步研究表明，晶状体表面小带的附着点有助于确定晶状体上皮细胞的边缘，并暗示BMP信号在这一过程中的作用。这一假设将在小鼠身上进行验证，小鼠的睫毛上皮非色素层中的纤维蛋白-1基因(Fbn1；成人眼睛中的主要纤维蛋白亚型)被有条件地删除。最后，在人类中，LTBP2的突变与早发性青光眼有关，LTBP2是一种微纤维相关蛋白。因此，我们将测试Ltbp2在 眼睛，并检查在小鼠中缺失Ltbp2是否会导致青光眼表型。总之，这些实验将提供对微纤维在眼睛发育和疾病中的作用的见解。由于微纤维介导的信号通路易于药物操纵，我们研究得出的见解可能有助于指导这些目前难以治愈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.