The long-term goal of our research program is to elucidate the role of cell adhesive interactions mediated by cadherins in the normal embryonic development of the neural retina and retinal pigment epithelium as well as in the continued maintenance of healthy mature retinal tissues. During the prior project period, we have made considerable progress in providing mechanistic insights into the function of retinal cadherins and the modes of their regulation of expression and function, while continuing to clarify issues regarding the timing and patterns of their expression. In order to continue our progress towards the long-term objectives of the project, an integrated series of new hypothesis-driven experiments is proposed to address the following specific aims.
SPECIFIC AIM 1. To (a) test the hypothesis that the epithelial-mesenchymal transformation of RPE cells induced by exposure to vitreous humor is caused by perturbations of cadherin expression and function, (b) characterize the vitriol factor mediating this activity, and (c) determine the consequences of perturbation of cadherin function on RPE differentiation.
SPECIFIC AIM 2. To test the hypotheses that (a) a membrane-associated retinal isoform of metalloprotease MMP-2 is responsible for regulation of N-cadherin turnover and generation of NCAD90, and (b) that NCAD90 mediates calcium signaling in the retina.
SPECIFIC AIM 3. To test the hypotheses that (a) the receptor tyrosine phosphatase PTPmu, and (b) cytoskeletal proteins such as vinculin, alpha- actinin and p120(cas) are associated with retinal cadherins and provide links in the cell signaling pathways which regulate retinal cadherin expression and function.
SPECIFIC AIM 4. To test the hypothesis that N- cadherin plays a critical role in development and maintenance of the retina by generating transgenic mice expressing dominant-negative forms of N-cadherin n a retinal tissue-specific manner.
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