The long-term goal of this research program is to determine the mechanisms whereby the integrin cell adhesion receptors regulate the normal embryonic development of the ocular lens. These receptors link the extracellular matrix to cytoskeletal associated signaling pathways which are involved in the regulation of cell adhesion, proliferation, migration, differentiation and apoptosis, all important processes in lens development. This proposal is focused on two integrins which we have shown to be important to embryonic lens development. We have shown that alpha5 integrin, whose expression is limited to lens epithelial cells, is linked to receptors for bFGF. We will determine whether the function of alpha5 in lens cell proliferation is regulated by this association. Concurrent with lens cell differentiation, the expression of alpha6 integrin isoform switches from alpha6B to alpha6A. We will determine whether the alpha6A isoform provides signals necessary for lens cell differentiation. Immunoprecipitation studies demonstrated that there is a differentiation specific association of the IGF-1 receptor (IGF-1R) with alpha6 integrin. We propose that the stimulation of lens fiber differentiation by IGF-1R requires its association with alpha6 integrin. These studies will provide crucial information about the mechanisms by which extracellular signals regulate lens development. In addition, they will show how perturbation of integrins and their associated signaling pathways may lead to lens pathologies and furnish insight into the processes that result in the formation of secondary cataracts following cataract surgery. The studies outlined in the following specific aims will support our hypotheses that alpha5 participates in the regulation of cell proliferation through its association with FGF receptors and that alpha6 integrin regulates lens cell differentiation through its association with IGF-1R:
Specific Aim 1. Verify our hypothesis that alpha5 integrin is required for the regulation of lens cell proliferation and for the migration of these cells prior to the initiation of their differentiation.
Specific Aim 2. Investigate the hypothesis that the proliferative and migratory function of alpha5 integrin in lens development is regulated by its interaction with migration of the differentiation cortical fiber cells and for regulation of the apoptotic events that accompany fiber cell differentiation.
Specific Aim 4. Investigate the hypothesis that alpha6 integrin function in lens cell migration, differentiation and/or apoptosis is regulated by its association with the IGF-1 receptor.
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