Pharmacological control of genetic deficient in corneal dystrophies

凝胶样滴状角膜营养不良(GDLD)是一种以严重的角膜淀粉样变性为特征的常染色体隐性遗传病。由于GDLD是最严重的角膜营养不良之一，因此我们重点研究GDLD。已分离到M1S1基因作为致病基因，并检测到致病突变。在本研究中，我们的蛋白质表达分析表明，正常的M1S1产物聚集在细胞与细胞的接触边界，而突变产物没有。我们和其他研究人员表明，GDLD中的淀粉样沉积含有乳铁蛋白。这些突变导致细胞-细胞黏附功能紊乱，并参与淀粉样蛋白沉积的发病机制。角膜上皮的病理状态可能允许泪液在角膜组织内积聚乳铁蛋白。我们的研究表明，乳铁蛋白在角膜组织中诱导了一些炎症介质，肥大细胞糜酶也降低了角膜上皮细胞的屏障功能。我们推测，药物增强细胞黏附和控制糜酶相关介质的表达可能会降低GDLD的严重程度。外源层粘连蛋白-5的应用和JAM-1基因的上调目前正在应用于体外实验。抑制糜酶活性的药理筛选也在进行中。

Gelatinous drop-like corneal dystrophy (GDLD) is an autosomal recessive disorder characterized by severe corneal amyloidosis. We focused on the studying of GDLD, because it is one of the most server corneal dystrophies. M1S1 gene had been isolated as a responsible gene and detected the disease-causing mutations. In this study, our protein expression analysis showed that the normal M1S1 product was accumulated at the cell-to-cell contact borders, but the mutant product did not. We and other researchers showed that the amyloid deposits in GDLD contain lactoferrin. The mutations result in a disturbance of cell-cell adhesion function and contribute to the pathogenesis of amyloid deposition. The pathological condition of corneal epithelium may allow the accumulation of lactoferrin within corneal tissue from the tears. Our studies show that some inflammatory mediators are induced in corneal tissue by lactoferrin and also the mast cell chymase also decreases the barrier function of corneal epithelial cell. We hypothesize that pharmacological enhancement of cell adhesion and controlling the expression of chymase-related mediators may reduce the severity of GDLD phenotype. The exogenous laminin-5 application and up-regulation of JAM-1 gene are now applying for in vitro experiments. And pharmacological screening for suppression of chymase activity is also ongoing.