The long term goal is to understand the role of insulin receptors (IR) in the retina and elucidate the intracellular signaling pathways they generate. The overall goal of this proposal is to gain new understanding of the control of photoreceptor function. The specific objective is to investigate the role of the retinal IR in regulation of photoreceptor structure and function. We made the novel finding that light stimulates tyrosine phosphorylation of the b-subunit of IR in vivo, and, in turn, activate phosphoinositide 3-kinase, a cell survival factor. The light effect is localized to photoreceptor neurons and is independent of insulin secretion. We have identified Grb14 an upstream regulator of IR (IR) requires photobleaching of rhodopsin for membrane targeting. Further Grb14 is an inhibitor of protein tyrosine phosphatase PTP1 b which specially dephosphorylates the IR. These observations led to the hypothesis that a light signal initiates the localization of Grb14 to photoreceptor outer segment membranes which leads to the inhibition of PTP1 b resulting in the protection of IR phosphorylation. Thus, the light-induced IR activation promotes photoreceptor survival and maintenance. The newly discovered pathway may have implications in other aspects of photoreceptor signaling. The following specific aims are designed to test our central hypothesis that light-induced activation of IR is important for normal photoreceptor survival and maintenance.
Aim 1 is to determine whether the IR in photoreceptor cells is necessary for light activation of survival pathways.
Aim 2 is to determine the mechanism of regulation of the IR by Grb14 and PTP1b.
Aim 3 is to determine the domains of Grb14 that are required for light-dependent translocation in rod photoreceptor cells. We will utilize a combination of genetic, molecular and biochemical approaches to address the novel biology of the pathway. Together, these studies will provide novel insights into the molecular regulation of photoreceptor structure and function by light. The information gained will be important for understanding the novel biology of the newly discovered pathway in rod photoreceptor. Results of these studies will help better understanding the mechanism of retinal degenerations and guide targets for future therapeutic intervention. The biological implications extend to the cause and treatment of a number of retinal degenerative diseases. ? ? ?
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