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.
