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Ion transport in health and disease. Emerging roles for Ca2+ signaling and endosomal pH in cancer, autism and neurodegenerative disorders
The Rao laboratory studies the role of novel ion transporters in human health and disease. One project focuses on the calcium signaling in breast cancer. We showed that an isoform of the secretory pathway Ca2+-ATPase, SPCA2, interacts with ion channels to drive tumor proliferation. We are currently investigating how downregulation of SPCA2 promotes epithelial to mesenchymal transition. A second project relates to the endosomal Na+/H+ exchangers NHE6 and NHE9 that are linked to autism, Christianson syndrome, ADHD and a growing list of neurodevelopmental and neurodegenerative disorders. We use a powerful PheWAS approach combined with model structure-driven evolutionary conservation analysis and functional screening of human variants to identify, evaluate and predict causality of autism-associated mutations. Loss of eNHE function results in hyperacidic endosomes, which increases amyloidogenic processing, and turnover of cell surface receptors and neurotransmitter transporters to impact neurotransmitter uptake and synaptic development. On the other hand, overexpression of NHE9 in glioblastoma confers chemoradiation resistance due to “inside out” control of oncogenic signaling. Our lab also discovered NHA2, an unusual Na+/H+ exchanger that is implicated in essential hypertension and plays a role in salt handling in the kidney. We make extensive use of 3D/organoid cultures, confocal microscopy, live cell calcium and pH imaging, and phenotype complementation in yeast to investigate mammalian transport proteins.
Prasad H, Rao R. Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH. Proc Natl Acad Sci U S A. 2018 Jul 10;115(28):E6640-E6649. doi: 10.1073/pnas.1801612115.
Kondapalli, K.C., Llongueras, J.P., Capilla-Gonzalez, V., Hack, A., Smith, C., Guerrero-Cazares, H., Quinones-Hinojosa, A., and Rao, R. (2015) A leak pathway for luminal protons in endosomes drives oncogenic signaling in glioblastoma. Nat. Commun. 6, 6289. doi: 10.1038/ncomms7289
Prasad, H. and Rao, R. (2015) The Na+/H+ exchanger NHE6 modulates endosomal pH to control processing of amyloid precursor protein in a cell culture model of Alzheimer Disease. J. Biol. Chem. 290: 5311-27.
Kondapalli, KC, Hack A, Schushan M, Landau, M, Ben-Tal N and Rao R. (2013) Functional evaluation of autism associated mutations in NHE9. Nat. Commun. 4:2510. doi: 10.1038/ncomms3510.
Feng, M., Grice, D., Faddy, H.M., Ngyuen, N., Leitch, S., Wang, Y., Muend, S., Kenny, P.A., Sukumar, S., Roberts-Thomson, S., Monteith, G., and Rao, R. (2010). Store-independent activation of Orai1 by SPCA2 in mammary tumors. Cell 143:84-98.