Rajini Rao, PhD.
The Rao laboratory studies the role of ion transport in health and disease. We use yeast as a model organism to uncover fundamental mechanisms in salt tolerance, calcium signaling, manganese detoxification, pH control and vesicle trafficking that are common to microbes, plants and animals. Our studies led to the recognition of a new family of Golgi/secretory pathway calcium/manganese ATPases (SPCA). Haploinsufficiency of human SPCA1 leads to Hailey Hailey disease characterized by severe ulceration of the skin. We recently demonstrated functional expression of hSPCA1 in yeast en route to understanding the molecular basis for the disease in human. We are beginning to investigate the role of SPCA in Mn2+ detoxification by the liver. Excessive exposure to this essential trace element is characterized by Mn2+ accumulation in the brain and Parkinson disease-like symptoms. Our laboratory has also identified the first intracellular/endosomal Na+/H+ exchanger named NHX1. Homologues of this transporter are found in all organisms where they play diverse roles ranging from salt tolerance, determination of flower color, to lysosome biogenesis. In collaboration with other laboratories, we are screening drugs that specifically inhibit the novel classes of transporters represented by the Golgi Ca2+-ATPase and endosomal Na+/H+ exchanger. For example, NHE inhibitors are useful in the treatment of ischemic hearts, and inhibition of Mn2+ transport may have anti-retroviral effects relating to the Mn2+-inhibition of reverse transcriptases. We use high throughput screens of yeast growth under conditions that clearly distinguish the phenotypes of wild type and null mutants. Recently, we showed that the anti-arrhythmic drug amiodarone exhibits potent fungicidal activity by disrupting calcium homeostasis. Since low doses of amiodarone are strongly synergistic with over-the-counter fungistatic drugs, we are exploring the potential use of this drug to treat fungal infections common to immunocompromised patients.
- Ton, V.-K., Mandal, D., Vahadji, C., and Rao, R. (2002) Functional Expression in Yeast of the Human Secretory Pathway Ca2+/ Mn2+--ATPase defective in Hailey Hailey disease. J. Biol. Chem. 277, 6422-6427
- Brett, C.L., Wei, Y., Donowitz, M., and Rao, R. (2002) Human Na+/H+ Exchanger NHE6 is Found in the Recycling Endosomes of Cells, Not Mitochondria. Am J Physiol Cell Physiol. 282, C1031-1041
- Sen Gupta, S., Ton, V.K., Beaudry, V., Rulli, S., Cunningham, K.W., and Rao, R. (2003) Antifungal activity of amiodarone is mediated by disruption of calcium homeostasis. J. Biol. Chem. 278, 28831-28839
- Ali, R., Mukherjee, S., Brett, C.L., and Rao, R. (2003) Inhibition of sodium/proton exchange by a Rab-GTPase activating protein regulates endosomal traffic in yeast. J. Biol. Chem. 278, in press (epub November 11)