LUMICAN AND EYE DEVELOPMENT AND FUNCTIONS

Lumcan是角膜基质的主要蛋白多糖成分， 据信在角膜透明度中起着关键作用。在角膜中， 透明度与抗拉强度通过高度有序的阵列相结合 直径均匀细小的胶原纤维。鲁米肯抑制药物 胶原纤维的侧向生长在体外可能有类似的 对角膜中胶原纤维形成的影响。硫酸角蛋白 鲁米肯的糖胺多聚糖侧链保持水分并帮助 保持透明所需的原纤维间距。这个 鲁米肯对胶原蛋白影响的分子相互作用 人们对纤维知之甚少。PI初步结果还表明 LUMICAN在发育中的角膜基质中很早就有表达， 这暗示了这种蛋白多糖在角膜发育中的潜在作用。 本研究的目的是阐明鲁米肯在角膜中的作用。 第一个目标是定义LUMICAN的分子机制 与胶原蛋白的相互作用，并深入了解这一重要方面 卢肯在角膜中的功能。这一目标将决定 结合动力学和鉴定LUMICAN核心蛋白上的 活跃于胶原蛋白结合，抑制纤维的侧向生长。 第二个目的是确定鲁米肯是否能抑制细胞与 胶原蛋白或纤维连接蛋白底物，因此，可能调节 角膜发育过程中间充质细胞的黏附/迁移 斯特尔玛。第三个目标是通过有针对性的方法产生缺光小鼠。 LUMICAN基因缺失及其对发育的影响 眼睛和角膜的结构和功能。 这项研究中提出的体外实验将识别 LUMICA核心蛋白未来的重要功能区域 鲁米肯在体内的定点突变研究。靶向基因 本研究中提议的删除LUMICA将首次， 阐述了它在体内的作用以及它的缺失对 眼角膜。一般来说，长期目标是开发小鼠模型。 用于角膜营养不良的另一种结缔组织疾病 蛋白多糖-胶原蛋白基质。

Lumican is a major proteoglycan component of the corneal stroma and believed to play a pivotal role in corneal transparency. In the cornea, transparency is combined with tensile strength by a highly ordered array of collagen fibrils of uniformly thin diameter. Lumican inhibits lateral growth of collagen fibrils in vitro and may have a similar effect on collagen fibril formation in the cornea. The keratan sulfate glycosaminoglycan side chains of lumican retain water and help to maintain interfibrillar spacing necessary for transparency. The molecular interactions underlying lumican's influence on collagen fibrils are poorly understood. The PI preliminary results also indicate that lumican is expressed very early in the developing corneal stroma, implying a potential role for this proteoglycan in corneal development. The purpose of this study is to elucidate lumican's role in the cornea. The first aim is to define the molecular mechanism underlying lumican's interactions with collagen and gain insight into this important aspect of lumican's function in the cornea. this aim will determine the binding kinetics and identify sites on the lumican core protein that are active in collagen-binding and inhibiting lateral growth of fibrils. The second aim is to determine if lumican inhibits cell adhesion to collagen or fibronectin substrates, and thus, likely to regulate mesenchymal cell adhesion/migration during development of the corneal stroma. The third aim is to generate lumican-deficient mice by targeted deletion of the gene for lumican and determine its effect on development of the eye and structure and functions of the cornea. The in vitro experiments proposed in this study will identify functionally important regions of the lumican core protein for future site-directed mutagenesis studies of lumican in vivo. The gene targeted deletion of lumican proposed in this study will, for the first time, address its role in vivo and the overall effect of its absence on the cornea. Generally, the long term objectives are to develop mouse models for corneal dystrophies another connective tissue disorders with altered proteoglycan-collagen matrices.