Lens Basement Membrane in SPARC-Null Cataractogenesis

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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.