EXTRACELLULAR MATRIX ABNORMALITIES IN CORNEAL EDEMA

人工晶状体型和无晶状体型大泡性角膜病变(PBK/ABK)是一种视力- 危害性角膜病变是最常见的 美国的角膜移植。它们造成了重大的 视力障碍导致办公室就诊的高昂医疗费用， 住院和外科手术。 血管内皮细胞数量减少和/或功能障碍 PBK/ABK患者的液体泵送能力导致慢性角膜水肿 眼角膜。然而，我们的初步研究发现，主要的细胞外 不易发生的PBK/ABK角膜基质(ECM)异常 只能用改变的液体平衡来解释。最引人注目的是 Tenascin的出现，这是一种已知的抗粘连特性的蛋白质， 它在PBK/ABK角膜中大量存在，但完全缺乏 来自正常的角膜。此外，我们还发现了纤维连接蛋白的变化， 减少层粘连蛋白和粘连蛋白，改变胶原表型。拿走 这些共同代表了PBK/ABK内发生的纤维化过程 眼角膜。 我们的工作假设是Tenascin和其他异常(纤维化) 人工晶状体眼/无晶状体眼大疱性病变中发现的细胞外基质 角膜病变对粘附剂迁移和功能的影响 内皮细胞的特性。 在本提案中，我们将(1)表征Tenascin和ECM中的成分 移植前早期PBK/ABK的角膜。这将使我们能够 确定这些矩阵相对于 疾病的发展。我们将(2)鉴定Tenascin剪接变体，因为 每一个都有独特的功能特征，以及(3)它们的细胞 起源。我们将(4)研究Tenascin对粘附性的影响。 角膜细胞的迁移、生长和液体泵功能。最后，我们 将(5)调查PBK/ABK中存在的增长因素 可能影响Tenascin和ECM表达的角膜。

Pseudophakic and aphakic bullous keratopathy (PBK/ABK) are vision- threatening cornea disorders which are the most common indications for corneal transplantation in the United States. They cause significant visual disabilities that lead to high medical costs for office visits, hospital stays and surgical procedures. Decreased numbers of endothelial cells and/or functional impairment of their fluid pumping ability lead to chronic corneal edema in PBK/ABK corneas. However, our preliminary studies identified major extracellular matrix (ECM) abnormalities in PBK/ABK corneas that cannot be easily explained only by an altered fluid balance. The most striking is the appearance of tenascin, a protein with known antiadhesive properties, which is found in abundance in PBK/ABK corneas but is completely absent from normal corneas. In addition, we found changes of fibronectin, decreased laminin and entactin, and altered collagen phenotype. Take together, these represent a fibrotic process occurring within the PBK/ABK corneas. Our working hypothesis is that tenascin and other abnormal (fibrotic) extracellular matrix found in the pseudophakic/aphakic bullous keratopathy corneas influence adhesives migratory and functional properties of the endothelial cells. In this proposal we will (1) characterize tenascin and ECM components in corneas with early PBK/ABK before transplantation. This will allow us to determine the temporal occurrence of these matrices in relation to the disease progression. We will (2) identify tenascin splice variants since each has unique functional characteristics, and (3) their cellular origin. We will (4) study the influence of tenascin upon the adhesion, migration, growth and fluid pump function of corneal cells. Finally, we will (5) investigate growth factors which are present in the PBK/ABK corneas that may influence tenascin and ECM expression.