Phosphoinositides are low-abundance membrane phospholipids which act as important recognition sites for a host of membrane associated proteins involved in intracellular signal transduction cascades, and in intracellular membrane biogenesis, homeostasis, and trafficking. Previously, their low abundance has precluded quantification of their levels in retinal photoreceptor neurons, but we have recently developed methods that allow accurate measurements of unprecedented sensitivity. These measurements have revealed striking light-induced increases in levels of PI(4,5)P2, its precursor, PI(4)P, and PI(3)P, without measurable increases in PI(3,4,5)P3. These results contrast with previous reports of light driven decreases in PI (4, 5) P2, and light activation of a PI-3 kinase isoform tht produces PI (3, 4, and 5) P3, and they reveal previously unknown pathways of light responses in photoreceptors. Retinal degeneration induced by a rod-specific knockout of the type III PI-3 kinase which produces PI (3) P underscores the physiological importance of phosphoinositide synthesis. We will use a range of techniques to manipulate gene expression or activity of enzymes of lipid metabolism in photoreceptors, along with multi-scale analysis of retinal structure, electrophysiological and behavioral measures of retinal function, and our innovative methods for quantifying and localizing specific phosphoinositides, to determine the molecular mechanisms for regulation of photoreceptor phosphoinositide levels and their roles in retinal function, health, and disease.
Rod and cone photoreceptor cells in our retina, responsible for detecting light in human vision, contain highly charged lipids belonging to a special class known as phosphoinositides, which regulate cell membrane formation, recycling, and renewal in many cell types. We will test the idea that light-regulated changes in phosphoinositide levels are important for maintaining a healthy retina in responses to excessive light or other environmental stresses, and serve to protect us from retinal neurodegeneration; if this idea is borne out, it would point to new therapeutic approaches for a range of degenerative diseases of the retina, such as retinitis pigmentosa, age-related macular degeneration, and diabetic retinopathy.
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