个人简介

Director, NIH International Center of Excellence for Malaria Research in South Asia (South Asia ICEMR) (2010-2017) Grand Challenges Explorations Award, Bill & Melinda Gates Foundation (2009-2012) Co-chair, Molecular Parasitology Meeting, Marine Biological Labs, Woods Hole, MA (2007-2009) Co-chair, Drugs Against Parasitic Diseases Keystone Meeting, Copper Mountain, CO (2005) Senior Scholar Award, Global Infectious Diseases, Ellison Medical Foundation (2002) Molecular, Cellular, and Immunology of Parasites Award, American Society of Tropical Medicine and Hygiene (2002) Module Director, Biology of Parasitism Course, Marine Biological Labs, Woods Hole, MA (2000-2002) New Initiatives in Malaria Research Award, Burroughs Wellcome Fund (1997-2000) Visiting Professor and Lecturer in Biochemistry, Stanford University Medical Center, CA (1995-2002) Tropical Medicine and Parasitology Study Section, NIH (1995-2000) Research Career Development Award, NIAID NIH(1994-1999) First Independent Research Support and Transition (FIRST) AWARD, NIAID NIH (1988-1993)

研究领域

Malaria Pharmacology/Functional Genomics

Malaria is a major cause of morbidity and mortality in the world, with about two million deaths and over 500 million infections per year. With the emergence of resistance against traditional drugs, there is an urgent need for new, affordable medicines against Plasmodium. Faithful, disciplined application of chemical principles to increasingly sophisticated understanding of biology can lead to new drug targets, candidate drugs, and can help reveal new principles in biology. The Rathod group currently pursues four main research directions in the area of malaria pharmacology. Targeting Pyrimidine BiosynthesisThe Rathod group is targeting high-value pyrimidine biosynthesis enzymes with selectivity by starting with host-parasite protein differences at the active-site, by appropriate pro-drugs, by supplementing non-selective antifolates with rescuing nutrients that only the host can use, or by disrupting unique protein-protein interactions. The enzymes targeted by the group are malarial thymidylate synthase and dihydroorotate dehydrogenase (the latter with M. Phillips at the University of Texas Southwestern Medical Center). Mutator PhenotypesThe Rathod group now has a detailed model for the phenotype which drives the acquisition of drug resistance in malaria parasites and has identified the genomic loci involved in the process. System-Wide Differences in Gene RegulationThe Rathod group discovered that some malarial drug targets may be uniquely sensitive to inhibitors in part due to tight parasite-specific protein-nucleic acid interactions. Such insights have allowed for improved strategies for expressing malaria proteins in the functional form. New Tools for Malaria ResearchThe Rathod group is creating and employing new tools and techniques to assist in research, including: 1) DNA microarrays, used to understand malaria gene regulation, particularly in the context of drug action; 2) QTL mapping, which assists in the dissection of resistance traits and control of gene expression; 3) Microfluidics, used to help model malaria pathobiology; and 4) Cell-free protein expression, which allows access to functional malarial proteins.

近期论文

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Herricks, T.; Seydel, K.B.; Molyneux, M.; Taylor, T.; Rathod, P.K. "Estimating physical splenic filtration of Plasmodium falciparum-infected red blood cells in malaria patients." Cellular Microbiology 2012 (in press). PMID:22892025 Marwaha, A.; White, J.; El Mazouni, F.; Creason, S.A.; Kokkonda, S.; Buckner, F.S.; Charman, S.A.; Phillips, M.A.; Rathod, P.K. "Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against Plasmodium falciparum dihydroorotate dehydrogenase." J. Med. Chem. 2012, 55(17), 7425-7436. PMID: 22877245 Narayanasamy, K.; Chery, L.; Basu, A.; Duraisingh, M.T.; Escalante, A.; Fowble, J.; Guler, J.L.; Herricks, T.; Kumar, A.; Majumder, P.; Maki, J.; Mascarenhas, A.; Rodrigues, J.; Roy, B.; Sen, S.; Shastri, J.; Smith, J.; Valecha, N.; White, J.; and Rathod, P.K. "Malaria evolution in South Asia: knowledge for control and elimination." Acta Trop. 2012, 121(3), 256-266. PMID: 22266213 Kumar, A.; Chery, L.; Biswas, C.; Dubhashi, N.; Dutta, P.; Dua, V.K.; Kacchap, M.; Kakati, S.; Khandeparkar, A.; Kour, D.; Mahajan, S.N.; Maji, A.; Majumder, P.; Mohanta, J.; Mohapatra, P.K.; Narayanasamy, K.; Roy, K.; Shastri, J.; Valecha, N.; Vikash, R.; Wani, R.; White, J.; and Rathod P.K. "Malaria in South Asia: prevalence and control." Acta Trop. 2012, 121(3), 246-255. PMID: 22248528 Herricks, T.; Seydel, K.B.; Turner, G.; Molyneux, M.; Heyderman, R.; Taylor, T.; and Rathod, P.K. "A microfluidic system to study cytoadhesion of Plasmodium falciparum infected erythrocytes to primary brain microvascularendothelial cells." Lab Chip. 2011, 11(17), 2994-3000. PMID: 21743938 Kumar, A.; Dua, V.K.; Rathod, P.K. "Malaria-attributed death rates in India." The Lancet 2011, 377(9770), 991-992. Larson, E.T.; Mudeppa, D.G.; et al. "The crystal structure and activity of a putative trypanosomal nucleoside phosphorylase reveal it to be a homodimeric uridine phosphorylase." J. Mol. Biol. 2010, 396(5), 1244-1259. Deng, X.; Gujjar, R.; et al. "Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds." J. Biol. Chem. 2009, 284, 26999-27009. Herricks, T.; Antia, M.; and Rathod, P.K. "Deformability limits of Plasmodium falciparum-infected red blood cells." Cell Microbiol. 2009, 11, 1340-1353. Gujjar, R.; Marwaha, A.; et al. "Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with anti-malarial activity in mice." J. Med. Chem. 2009, 52 (7), 1864-1872. Ganesan, K.; Ponmee, N.; Jiang, L.; Fowble, J.W.; White, J.; Kamchonwongpaisan, S.; Yuthavong, Y.; Wilairat, P.; Rathod, P.K. "A genetically hard-wired metabolic transcriptome in Plasmodium falciparum fails to mount protective responses to lethal antifolates." PLoS Pathog. 2008, 4(11): e1000214. PMC2581438 Gonzales, J.M.; Patel, J.J.; Ponmee, N.; Jiang, L.; Tan, A.; Maher, S.P.; Wuchty, S.; Rathod, P.K.; and Ferdig, M.T. "Regulatory Hotspots in the Malaria Parasite Genome Dictate Transcriptional Variation." PLoS Biol. 2008, 6(9): e238. PMC2581438 Antia, M.; Herricks, T.; and Rathod, P.K. "Microfluidic models for Malaria Pathogenesis." Cell. Microbiol. 2008, 10(10), 1968-1974 (Invited Review). PMID18754851 Phillips, M.A.; Gujjar, R.; Malmquist, N.A.; White, J.; El Mazouni, F.; Baldwin, J.; and Rathod, P.K. "Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite, Plasmodium falciparum." J. Med. Chem. 2008, 51, 3649-3653. PMC2624570 Hunter, J.H.; Gujjar, R.; Pang, C.K.T.; and Rathod, P.K. "Kinetics and Ligand-Binding Preferences of Mycobacterium tuberculosis Thymidylate Synthases, ThyA and ThyX." PLoS One 2008, 3(5): e2237. PMC2386288 Antia, M.; Herricks, T.; and Rathod, P.K. "Microfluidic modeling of cell-cell interactions in malaria pathogenesis." PloS Pathogens 2007, 3:e99. PMC1924869 Mudeppa, D.G.; Pang , C.K.T.; Tsuboi, T.; Endo, Y.; Buckner, F.S.; Varani, G.; and Rathod, P.K. "Cell-free production of functional Plasmodium falciparum dihydrofolate reductase-thymidylate synthase." Mol. Biochem. Parasitol. 2007, 151, 216-219. Shelby, J.P.; White, J.; Ganesan, K.; Rathod, P.K.; and Chiu, D.T. "A microfluidic model for single-cell capillary obstruction by Plasmodium falciparum-infected erythrocytes." Proc. Natl. Acad. Sci. USA 2003, 100, 14618-14622. Rathod, P.K. and Phillips, M.A. "Prized malaria drug target nailed." Nature Struct. Biol. 2003, 10, 316-318. Zhang, K. and Rathod, P. K. "Divergent regulation of dihydrofolate reductase between malaria parasite and human host." Science 2002, 296, 545-547.