病理性近视已成为全球范围内高患病率致盲性遗传眼病，以巩膜胶原纤维降解为主要表现的细胞外基质重塑是病理性近视发展的重要环节。申请者前期研究发现LUM(L199P)突变体小鼠眼轴延长、巩膜胶原纤维排列紊乱，提示LUM编码亮蛋白聚糖异常可能导致病理性近视的发生，但具体调控机制尚不明确。我们提出研究假说:亮蛋白聚糖通过调控MMP-14影响其下游MMP-2的表达，进而影响巩膜胶原纤维的合成/降解平衡，可能是病理性近视发生发展的分子机制之一。本研究拟先通过小鼠体内研究确定亮蛋白聚糖表达异常对巩膜胶原纤维的影响，然后构建LUM和MMP-14腺病毒转染人巩膜成纤维细胞，以期从组织细胞及分子水平探索亮蛋白聚糖与MMP-14相互作用。MMP-14定位于细胞膜，是介导激活下游多种MMPs的关键环节，深入了解其作用机制并进一步探索针对这一环节的干预手段，可为临床防控病理性近视进展的药物研发提供直接实验依据。

Pathological myopia (PM) has become a worldwide, high-prevalence, hereditary eye disease that can lead to blindness. Sclera remodeling is important in the development and progression of PM mainly present as collagen degradation. Our previous work in LUM (L199P) transgenic mice revealed its elongated axial length and disordered scleral collagen fiber arrangement, suggesting that LUM encoded anomaly might cause PM. Whereas the underlying regulation mechanisms were unclear. We hypothesize that lumican affects the expression of sclera collagen fibers via its regulation on MMP-14 and its downstream component MMP-2, which may be one of the molecular mechanisms for the development of pathological myopia. In this study, we firstly plan to analyze the effect of mutant lumican on scleral collagen fibers in mouse in vivo, and then investigate the mutual effect of lumican and MMP-14 with LUM/MMP-14-transfected human scleral fibroblasts in cellular and molecular level. MMP-14 locates in the cell membrane, and places in the key segment activating multiple extracellular MMPs downstream. It is meaningful and worthwhile to understand the mechanism and investigate of intervention method aiming at MMP-14. This study can provide direct evidence for novel drug research of PM control in the future.