EXTRACELLULAR MATRIX ABNORMALITIES IN CORNEAL EDEMA

人工晶状体和无晶状体大泡性角膜病变（PBK/ABK）是视力- 威胁性角膜疾病是最常见的适应症， 角膜移植在美国它们会造成严重的 视力残疾导致办公室访问的高额医疗费用， 住院和外科手术。 内皮细胞数量减少和/或 在PBK/ABK中，它们的液体泵送能力导致慢性角膜水肿 角膜然而，我们的初步研究发现， 在PBK/ABK角膜中的基质（ECM）异常， 只能用体液平衡改变来解释最引人注目的是 腱生蛋白，一种具有已知抗粘附特性的蛋白质， 其在PBK/ABK角膜中大量存在，但完全不存在 正常的角膜。此外，我们还发现了纤维连接蛋白的变化， 层粘连蛋白和巢蛋白减少，胶原表型改变。采取 这些共同代表了在PBK/ABK内发生的纤维化过程 角膜 我们的工作假设是，腱生蛋白和其他异常（纤维化） 在人工晶状体/无晶状体大疱中发现的细胞外基质 角膜病变对粘合剂迁移和功能影响 内皮细胞的特性。 在本提案中，我们将（1）表征肌腱蛋白和ECM组分， 在移植前给予早期PBK/ABK。这将使我们能够 确定这些矩阵相对于 疾病进展。我们将（2）鉴定腱蛋白剪接变体， 每一种都有独特的功能特征，（3）它们的细胞 起源我们将（4）研究腱生蛋白对粘附的影响， 角膜细胞的迁移、生长和液体泵功能。最后我们 将（5）研究存在于PBK/ABK中的生长因子 可能影响腱生蛋白和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.