Normal visual function is dependent on maintenance of the close structural and functional interactions between the RPE-ller-photoreceptor cells. The retina has a high rate of metabolism, which is supported by oxidative and glycolytic catabolism of metabolic substrates. It is now clear that different cell types within a tissue can b metabolically coupled whereby lactate and ketone bodies generated by one cell type can be utilized by an adjacent cell to fuel oxidative phosphorylation. Monocarboxylate transporters (MCTs) have been shown to play a key role in the shuttling of metabolites between astrocytes and neurons as well as between stromal fibroblast and cancer cells. In the outer retina we propose that there is metabolic coupling between RPE-Mller-photoreceptor cells that is facilitated by the unique array of MCTs expressed in each cell type. Consistent with this hypothesis are studies of the CD147 (Bsg) null mouse where loss of MCT1, MCT3 and MCT4 expression and profound decreases in outer retinal function and survival may all be linked to changes in energy metabolism due to loss of MCT expression. To determine the specific contribution of MCT1 and MCT4 and glucose metabolism to maintaining the functional activity and survival of photoreceptor cells we have proposed the following Specific Aims: 1. Test the hypothesis that glycolytic metabolism of glucose by Mller cells is critical for photoreceptor cell function and survival;2. Test the hypothesis that both glucose and lactate are required to support photoreceptor cell health and survival;3. Test the hypothesis that MCTs in the RPE support metabolic coupling and recycling of nutrients between the RPE and outer retina important for normal visual function. This research will use novel animal models to systematically determine the role of Glut1 and MCTs and will provide critical new insights into how metabolic coupling in the outer retina maintains visual function. Our finding will lay the groundwork for understanding mechanism through which metabolic changes could contribute to the pathophysiology of blinding diseases.
Normal visual function is dependent on maintenance of the close structural and functional interactions between the retina pigment epithelium, Mller cells and photoreceptor cells. In the outer retina we propose that there is metabolic coupling between RPE-Mller-photoreceptor cells that is facilitated by the unique array of monocarboxylate transporters expressed in each cell type. Altered expression or activity of these transporters could contribute to the pathophysiology of blinding diseases.
|Adijanto, Jeffrey; Philp, Nancy J (2014) Cultured primary human fetal retinal pigment epithelium (hfRPE) as a model for evaluating RPE metabolism. Exp Eye Res 126:77-84|
|Pfeffer, Bruce A; Philp, Nancy J (2014) Cell culture of retinal pigment epithelium: Special Issue. Exp Eye Res 126:1-4|
|Lehmann, Guillermo L; Benedicto, Ignacio; Philp, Nancy J et al. (2014) Plasma membrane protein polarity and trafficking in RPE cells: past, present and future. Exp Eye Res 126:5-15|
|Adijanto, Jeffrey; Du, Jianhai; Moffat, Cynthia et al. (2014) The retinal pigment epithelium utilizes fatty acids for ketogenesis. J Biol Chem 289:20570-82|
|Abplanalp, Jeannette; Laczko, Endre; Philp, Nancy J et al. (2013) The cataract and glucosuria associated monocarboxylate transporter MCT12 is a new creatine transporter. Hum Mol Genet 22:3218-26|
|Adijanto, Jeffrey; Philp, Nancy J (2012) The SLC16A family of monocarboxylate transporters (MCTs)--physiology and function in cellular metabolism, pH homeostasis, and fluid transport. Curr Top Membr 70:275-311|
|Adijanto, Jeffrey; Castorino, John J; Wang, Zi-Xuan et al. (2012) Microphthalmia-associated transcription factor (MITF) promotes differentiation of human retinal pigment epithelium (RPE) by regulating microRNAs-204/211 expression. J Biol Chem 287:20491-503|
|Whitaker-Menezes, Diana; Martinez-Outschoorn, Ubaldo E; Lin, Zhao et al. (2011) Evidence for a stromal-epithelial ""lactate shuttle"" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle 10:1772-83|
|Castorino, John J; Deborde, Sylvie; Deora, Ami et al. (2011) Basolateral sorting signals regulating tissue-specific polarity of heteromeric monocarboxylate transporters in epithelia. Traffic 12:483-98|
|Castorino, John J; Gallagher-Colombo, Shannon M; Levin, Alex V et al. (2011) Juvenile cataract-associated mutation of solute carrier SLC16A12 impairs trafficking of the protein to the plasma membrane. Invest Ophthalmol Vis Sci 52:6774-84|
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