Signaling Roles of Phosphoinositide Lipids in the Retina.
Phosphoinositides (also known as phosphatidylinositol phosphates, or PIPs) are universal signaling molecules that directly interact with membrane proteins or with cytosolic proteins containing domains that directly bind PIPs and are recruited to cell membranes. Through the activities of phosphoinositide kinases and phosphoinositide phosphatases, seven distinct phosphoinositide lipid molecules are formed from the parent molecule, phosphatidylinositol. PIP signals regulate a wide range of cellular functions, including cytoskeletal assembly, membrane budding and fusion, ciliogenesis, vesicular transport, and signal transduction. Changes in the expression and activity of PIP-kinases and PIP-phosphatases have been implicated in retinal degeneration. Our lab is investigating the function and mechanism of activation of PIP-modifying enzymes/phosphatases and further unraveling PIP regulation and function in the different cell types of the retina.
Endogenous Neuroprotective Pathways in the Retina
Every day, our eyes are exposed to copious amounts of light, and the endogenous neuroprotective pathways in the retina act as molecular sunglasses. Several neuroprotective pathways have been identified in the retina in response to stress; however, the pathway(s) that provide daily neuroprotection are yet to be determined. The insulin-like growth factor 1 receptor (IGF-1R) is a receptor tyrosine kinase that mediates the actions of IGF1, which binds with high affinity and is expressed in the retina and photoreceptor cells. Human carriers of homozygous mutations associated with reduced expression of the IGF-1R ligand, Igf1 gene, have mental retardation and deafness, which are associated with severe prenatal growth retardation, postnatal growth failure, and microcephaly. Global IGF-1 KO mice have been shown to have an age-related visual loss in addition to congenital deafness. Our recent studies showed that loss of IGF-1R in photoreceptor cells resulted in retinal degeneration. Therefore, understanding the mechanism(s) involved in the activation and deactivation of IGF-1R should have implications for retinitis pigmentosa, age-related macular degeneration, and Usher syndrome. We are using retina cell-specific knockout models of IGF-1R and IGF-1 to define the mechanism of IGF-1R-mediated endogenous neuroprotective pathways.
Non-canonical Insulin Receptor Signaling Pathway in Photoreceptor Cells
Insulin receptors (IR) and insulin signaling proteins are widely distributed throughout the central nervous (CNS) system. Dysregulation of IR signaling in the CNS has been linked to the pathogenesis of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. We discovered that IR signaling in rods is controlled by growth factor receptor-bound protein 14 (Grb14), an upstream regulator of the IR, and requires photobleaching of rhodopsin for membrane targeting. Grb14 prevents IR dephosphorylation by protein tyrosine phosphatase 1B (PTP1B), a tyrosine phosphatase specific to the IR. Our recent studies established a down-regulation of IR signaling due to increased retinal PTP1B activity in animal models of retinitis pigmentosa, diabetic retinopathy, and Leber Congenital Amaurosis. Studies are underway in our laboratory to target PTP1B in these disease models. Our new and innovative