Philp, Nancy J.
Nancy J. Philp, PhD
263 Alumni Hall
Philadelphia, PA 19107
(215) 923-3808 fax
PhD, University of Michigan - 1995
Associate Professor, Department of Pathology, Anatomy & Cell Biology
Co-Director, Cell Biology & Regenerative Medicine Graduate Program
Research and Clinical Interests
Research interest is a combination of monocarboxylate transporters; CD147; retinal pigmment epithelium; retinal metabolism; glycolysis, and JAM-C
The focus of my laboratory has been to study the expression, regulation and functional role of monocarboxylate transporters (MCTs) in maintaining metabolic homeostasis in the retina and normal vision. The Retina, like other neural tissue, has a high energy demand and is dependent on a continuous supply of oxygen and metabolic substrates from the blood to maintain visual activity. The primary energy substrate of the retina is glucose which is transported from the choroids blood supply to the outer retina by the retinal pigment epithelium (RPE). The majority of the glucose transported into the outer-retina is metabolized through anaerobic glycolysis in Müller glial cells thus producing large quantities of lactate which is utilized by photoreceptor cells to fuel oxidative phosphorylation and the excess lactate is transported out of the retina by the RPE.
We have taken an integrative approach in which we have combined genetic, biochemical, and imaging analysis to study the underlying molecular mechanisms. We characterized the expression of MCTs in the RPE and retina and identified a new member of this transporter family, MCT3. We showed that MCT3 is preferentially expressed in the basolateral membrane of the RPE and like MCT1 and MCT4; it requires association with an accessory protein, CD147 for efficient processing and trafficking to the plasma membrane. IN CD147 null mouse, which has impaired visual function; we found that there is a loss of MCT expression in the retina and the RPE suggesting that lactate homeostasis critical for visual function. Recently we generated a MCT3 null mouse and showed that there is a reduction in the amplitude of the rod photoreceptor a-wave and the rod and cone photoreceptor b-waves. The CD147 and the MCT3 null mice provide excellent model systems for studying how alterations in expression or distribution of these proteins could contribute to retinal disease.
Ongoing Projects in my lab include:
- Characterizing mechanisms regulating tissue specific trafficking of heteromeric transporter proteins in different epithelia.
- Identifying adaptor proteins that regulate trafficking of CD147 and MCT3 to the basolateral membrane and determine tissue specific and development patterns of expression.
- Characterizing the role of MCT12 in maintaining lens homeostasis and determine how mutations SLC16A12, an orphan member of the monocarboxylate acid transporter family cause age related and juvenile cataracts.
- Mechanism regulating age and disease related expressions of SLC16A8 in the retinal pigment epithelium.
- Investigate the dual role of tissue factor in the RPE: protecting the RPE against oxidative stress and enhancing the formation of epiretinal membranes after retinal detachment.
Most Recent Peer-Reviewed Publications
- Phagocytosis-dependent ketogenesis in retinal pigment epithelium
- Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development
- The retinal pigment epithelium utilizes fatty acids for ketogenesis implications for metabolic coupling with the outer retina
- Cell culture of retinal pigment epithelium: Special Issue
- Cultured primary human fetal retinal pigment epithelium (hfRPE) as a model for evaluating RPE metabolism
- Plasma membrane protein polarity and trafficking in RPE cells: Past, present and future
- Donor splice-site mutation in CUL4B is likely cause of X-linked intellectual disability
- The cataract and glucosuria associated monocarboxylate transporter MCT12 is a new creatine transporter
- The SLC16A family of monocarboxylate transporters (MCTs)-physiology and function in cellular metabolism, pH homeostasis, and fluid transport
- Microphthalmia-associated transcription factor (MITF) promotes differentiation of human retinal pigment epithelium (RPE) by regulating microRNAs-204/211 expression
- Mitochondrial metabolism in cancer metastasis: Visualizing tumor cell mitochondria and the "reverse Warburg effect" in positive lymph node tissue
- Using the "reverse Warburg effect" to identify high-risk breast cancer patients: Stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers
- Retinal pigment epithelial expression of complement regulator CD46 is altered early in the course of geographic atrophy
- Juvenile cataract-associated mutation of solute carrier SLC16A12 impairs trafficking of the protein to the plasma membrane
- Evidence for a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts
- Epithelial Domains
- Basolateral Sorting Signals Regulating Tissue-Specific Polarity of Heteromeric Monocarboxylate Transporters in Epithelia
- Modulation of MCT3 expression during wound healing of the retinal pigment epithelium
- Mice deficient in MCT8 reveal a mechanism regulating thyroid hormone secretion
- The absence of a clathrin adapter confers unique polarity essential to proximal tubule function