Lens Basement Membrane in SPARC-Null Cataractogenesis

描述（由申请人提供）：SPARC（分泌蛋白酸性和富含半胱氨酸），也称为骨连接素和BM-40，是一种基质细胞糖蛋白，已被证明可调节细胞功能，如细胞周期、细胞形状变化、迁移、粘附、基因表达和ECM产生。sparc缺失小鼠存活，但表现出100%的外显率白内障。晶状体囊是高度发达的晶状体基底膜（BM），是一种特殊的外基质结构，具有调节晶状体上皮细胞行为和分化的功能。SPARC作为一种主要的细胞-基质调节剂，定位于晶状体囊和晶状体上皮，可能在晶状体BM结构、基质组织及其与细胞内通路的连接以及晶状体细胞- ecm相互作用中发挥关键作用，而晶状体细胞- ecm相互作用的缺陷可能导致严重的病理后果，如白内障的形成。我们将验证SPARC缺失导致晶状体基底膜结构和功能完整性丧失的假设，并导致晶状体细胞- ecm相互作用的改变，从而导致白内障的发生。

DESCRIPTION (provided by applicant): SPARC (secreted protein acidic and rich in cysteine), also termed osteonectin and BM-40, is a matricellular glycoprotein which has been shown to regulate cell functions such as cell cycle, cell shape change, migration, adhesion, gene expression and ECM production. SPARC-null mice are viable but exhibit cataract with 100% penetrance. Lens capsule, a highly-developed lens basement membrane (BM), is a specialized ECM structure which functions to regulate cell behavior and differentiation of the lens epithelial cells. SPARC, as a major cell-matrix regulator that is localized in the lens capsule and lens epithelium, may play a pivotal role in the lens BM structure, matrix organization and its connections to intracellular pathways, and lens cell-ECM interactions, defects in which can have significant pathological consequences, such as cataract formation. We will test the hypothesis that the absence of SPARC contributes to a loss of the structural and functional integrity of the lens BM, and leads to alteration of lens cell-ECM interactions, that contribute to the generation of cataracts. Based on our understanding of SPARC structure and function, we propose three aims to test our hypotheses: 1) SPARC plays a pivotal role in structural stability and organization of the lens BM. Mice lacking SPARC will exhibit alterations of lens BM components and compromised lens capsule structure; 2) SPARC modulates lens epithelial cell adhesion through its regulation of the production of the adhesive proteins laminin 1 and fibronectin, and by its interaction with them; 3) Lens capsule permeability is compromised in SPARC-null lens, which contributes, in part, to the cataract formation in this model. The experiments proposed in this application will provide an understanding of the role of SPARC in the organization of ECM components, in cell-ECM interactions during lens development, and in the generation of cataracts in SPARC-null mice.