The retinal pigment epithelium (RPE) maintains retinal homeostasis by regulating the transport of ions, metabolites and fluid into and out of the neural retina. The long-term goal of this proposal is to characterize the role of RPE lactate transporters in maintaining normal retinal metabolism and to determine how changes in expression of these transporters could contribute to the pathophysiology of retinal disease. Transport of lactate into and out of cells is mediated by a family of proton-coupled monocarboxylate transporters (MCTs). During the past funding period, we established that the RPE expresses two MCTs; MCT1 in the apical membrane and MCT3 in the basolateral membrane. The polarized distribution of MCT1 and MCT3 in the RPE provides a mechanism for vectorial transport of lactate from the retina to the choroid, thereby regulating the pH and osmolarity in the space surrounding the photoreceptor cells. Alteration in the expression or polarization of these transporters would be expected to lead to photoreceptor cell degeneration. While MCT1 is widely expressed, MCT3 is preferentially expressed in the RPE. We cloned the mouse and human MCT3 genes and determined that the human gene maps to chromosome 22q12.3-13.2, a locus that has been associated with macular degeneration. Recently we have found that MCTs in the RPE are not isolated proteins but rather associate with a transmembrane glycoprotein- CD147. Like MCTs, CD147 is abundant in the apical and basolateral membranes of the RPE. In the CD147 null mice there is a loss of expression of MCTs in the RPE, suggesting that subunit assembly is required for targeting of MCT1 and MCT3 to the plasma membrane. In this competitive renewal application, we have proposed an integrated series of hypothesis driven experiments designed to further our understanding of the importance of MCT3 in maintaining normal visual function.
The Specific Aims of this project are: (1) to determine the mechanisms that regulate the biosynthesis, trafficking, and functional activity of MCT1 and MCT3 in the RPE; (2) to characterize the MCT3 promoter and identify elements that regulate developmental and tissue specific expression of the MCT3 gene; (3) to determine the effects of targeted deletion of the MCT3 gene on the viability and functional activity of photoreceptor cells.
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|Reyes-Reveles, Juan; Dhingra, Anuradha; Alexander, Desiree et al. (2017) Phagocytosis-dependent ketogenesis in retinal pigment epithelium. J Biol Chem 292:8038-8047|
|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; 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|
|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|
|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; 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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