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Translational Control of Disease

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Prabha Sampath

Trained at the Lerner Research Institute, Cleveland Clinic Foundation in United States, Dr. Prabha Sampath studied gene regulation during inflammation. As a postdoctoral fellow at the Center for Cardiovascular and Regenerative Medicine, University of Washington, Dr. Sampath worked on translational control mechanisms in embryonic stem cell differentiation. Dr. Sampath is the recipient of prestigious A*STAR Investigatorship award and she joined the Institute of Medical Biology, Singapore to set up her own research group in May 2008. She is now a Senior Principal Investigator at IMB, holds an adjunct position at Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore and Duke-NUS School of Medicine. Currently working on translation control of gene expression in multiple systems, Dr. Sampath’s projects are focused on identification of specific novel therapeutic targets. 

Protein translation is tightly regulated by the sequence and structural elements in the 3’ and 5’ untranslated regions of the transcript and its binding factors. Non-coding RNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), influence translation and its machinery.  Translational control of gene expression defines the proteome and differentially translated genes in a specific pathological condition mirror the spectrum of proteins synthesized. Research in my laboratory is mainly focused on exploring molecular mechanisms of translational regulation/dys-regulation in multiple pathological conditions including cancer and wound healing disorders especially in chronic non-healing wounds. Visualizing these interactions at the molecular level, our objective has been to identify specific novel therapeutic targets. 

On one of the cancer projects, we identified microRNA-138 as a prognostic biomarker for malignant gliomas, which are the most aggressive forms of brain tumor. As a potential therapeutic target, depletion of miR-138 prevents tumor growth in mouse models. 

On a wound healing project, we identified a dual-state molecular switch, which orchestrates wound re-epithelialization. A defective switch in chronic non-healing wounds prevents wound re-epithelialization and wound healing. Currently, we are working on a strategy to accelerate wound closure, increase efficacy of wound re-epithelialization and arrest progression of a fresh wound to a chronic non-healing wound.

 

Group Members

Senior Research Fellows
Gopinath Meenakshi Sundaram
  Srikanth Nama
Research Fellow Manish Muhuri
Postgraduate Students Federica Di Pascal (SINGA)
  Wen Chiy Liew (SINGA)
Research Officers
Muhammad Hisyam Ismail
  Ang Da Zhi, Nicholas
  Yeo Chee Wei, Paul

Winata CL, Łapiński M, Pryszcz L, Vaz C, Bin Ismail MH, Nama S, Hajan HS, Lee SGP, Korzh V, Sampath P, Tanavde V, Mathavan S. Cytoplasmic polyadenylation-mediated translational control of maternal mRNAs directs maternal-to-zygotic transition. Development. 2018 Jan 8;145(1). pii: dev159566. doi: 10.1242/dev.159566. Link
Winata CL, Łapiński M, Pryszcz L, Vaz C, Bin Ismail MH, Nama S, Hajan HS, Lee SGP, Korzh V, Sampath P, Tanavde V, Mathavan S. Cytoplasmic polyadenylation-mediated translational control of maternal mRNAs directs maternal-to-zygotic transition. Development. 2018 Jan 8;145(1). pii: dev159566. doi: 10.1242/dev.159566. Link
Sundaram GM, Sampath P. Carcinoma Cells Reprogram a Wound-healing Switch to Promote Metastasis. Mol Cell Oncol. 2018 Sep 20;5(6):e1432255. doi: 10.1080/23723556.2018.1432255. Link
Sundaram GM, Quah S, Sampath P. Cancer: the dark side of wound healing. FEBS J. 2018 Dec;285(24):4516-4534. doi: 10.1111/febs.14586. Link
Sundaram GM, Ismail HM, Bashir M, Muhuri M, Vaz C, Nama S, Ow GS, Vladimirovna IA, Ramalingam R, Burke B, Tanavde V, Kuznetsov V, Lane EB, Sampath P. EGF hijacks miR-198/FSTL1 wound-healing switch and steers a two-pronged pathway toward metastasis. J Exp Med. 2017 Oct 2;214(10):2889-2900. doi: 10.1084/jem.20170354. Link
Tan DSW, Chong FT, Leong HS, Toh SY, Lau DP, Kwang XL, Zhang X, Sundaram GM, Tan GS, Chang MM, Chua BT, Lim WT, Tan EH, Ang MK, Lim TKH, Sampath P, Chowbay B, Skanderup AJ, DasGupta R, Iyer NG. Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma. Nat Med. 2017 Oct;23(10):1167-1175. doi: 10.1038/nm.4401. Link
Pursani V, Pethe P, Bashir M, Sampath P, Tanavde V, Bhartiya D. Genetic and Epigenetic Profiling Reveals EZH2-mediated Down Regulation of OCT-4 Involves NR2F2 during Cardiac Differentiation of Human Embryonic Stem Cells. Sci Rep. 2017 Oct 12;7(1):13051. doi: 10.1038/s41598-017-13442-9. Link
Di Pascale F, Nama S, Muhuri M, Quah S, Ismail HM, Chan XHD, Sundaram GM, Ramalingam R, Burke B, Sampath P. C/EBPβ mediates RNA polymerase III-driven transcription of oncomiR-138 in malignant gliomas. Nucleic Acids Res. 2017 Nov 10. doi: 10.1093/nar/gkx1105 Link
Giannakakis A, Zhang J, Jenjaroenpun P, Nama S, Zainolabidin N, Aau MY, Yarmishyn AA, Vaz C, Ivshina AV, Grinchuk OV, Voorhoeve M, Vardy LA, Sampath P, Kuznetsov VA, Kurochkin IV, Guccione E. Contrasting expression patterns of coding and noncoding parts of the human genome upon oxidative stress. Sci Rep. 2015 May 29;5:9737. doi: 10.1038/srep09737 Link
Qu J, Ero R, Feng C, Ong LT, Tan HF, Lee HS, Ismail MH, Bu WT, Nama S, Sampath P, Gao YG, Tan SM. Kindlin-3 interacts with the ribosome and regulates c-Myc expression required for proliferation of chronic myeloid leukemia cells. Sci Rep. 2015 Dec 18;5:18491. doi: 10.1038/srep18491. Link
Yarmishyn AA, Batagov AO, Tan JZ, Sundaram GM, Sampath P, Kuznetsov VA, Kurochkin IV. HOXD-AS1 is a novel lncRNA encoded in HOXD cluster and a marker of neuroblastoma progression revealed via integrative analysis of noncoding transcriptome. BMC Genomics. 2014;15 Suppl 9:S7. doi: 10.1186/1471-2164-15-S9-S7. Epub 2014 Dec 8. PubMed PMID: 25522241; PubMed Central PMCID: PMC4290621. Link
Chan, X, H., Ramasamy, S., and Sampath, P., MicroRNA-mediated Translational Control in Stem Cells Self-renewal and Therapeutic Implications “miRNA in Regenerative Medicine” Elsevier Publications 2014
Chan, X, H., Nama, S., Sundaram, G., and Sampath, P., MicroRNA Therapeutics to Target Brain Tumor Stem Cells “Stem cells and Cancer” Wiley Publications 2014
Sundaram GM, Common JE, Gopal FE, Srikanta S, Lakshman K, Lunny DP, Lim TC, Tanavde V, Lane EB, Sampath P. 'See-saw' expression of microRNA-198 and FSTL1 from a single transcript in wound healing. Nature. 2013 Mar 7;495(7439):103-6. doi: 10.1038/nature11890. Epub 2013 Feb 10. PubMed PMID: 23395958. Link
Sundaram GM, Sampath P. Regulation of context-specific gene expression by posttranscriptional switches. Transcription. 2013 Sep-Dec;4(5):213-6. PubMed PMID: 24135704; PubMed Central PMCID: PMC4114540. Link
Commentary on "'See-saw' expression of microRNA-198 and FSTL1 from a single transcript in wound healing." See-Saw Gene Expression (2013) Science 339: 1253 Link
Commentary on "'See-saw' expression of microRNA-198 and FSTL1 from a single transcript in wound healing.". The Healing Switch (2013) Science Signaling 6: ec66 Link
Chan XH, Nama S, Gopal F, Rizk P, Ramasamy S, Sundaram G, Ow GS, Ivshina AV, Tanavde V, Haybaeck J, Kuznetsov V, Sampath P. Targeting glioma stem cells by functional inhibition of a prosurvival oncomiR-138 in malignant gliomas. Cell Rep. 2012 Sep 27;2(3):591-602. doi: 10.1016/j.celrep.2012.07.012. Epub 2012 Aug 24. PubMed PMID: 22921398. Link
Sampath P, Pritchard DK, Pabon L, Reinecke H, Schwartz SM, Morris DR, Murry CE. (2008) A hierarchical network controls protein translation during murine embryonic stem cell self-renewal and differentiation. Cell Stem Cell. 2(5):448-60.
Mazumder, B., Sampath, P., and Fox, P. L. (2006)Translational control of ceruloplasmin gene expression: beyond the IRE. Biol Res. 39(1):59-66.
Mazumder, B., Sampath, P., and Fox, P. L. (2005) Regulation of macrophage ceruloplasmin gene expression: one paradigm of 3'-UTR-mediated translational control. Mol Cells. 20(2): 167-72.
Sampath, P., Mazumder, B., Seshadri, V., Gerber, C.A., Chavatte, L., Kinter, M., Ting, S.M., Dignam, J.D., Kim, S., Driscoll, D. M., and Fox, P. L. (2004) Non-canonical Function of Glutamyl-prolyl-tRNA Synthetase: Gene-specific Silencing of Translation. Cell 119, 195-208.
Sampath, P., Mazumder, B., Seshadri, V., and Fox, P.L. (2003) Transcript-selective translational silencing by gamma interferon is directed by a novel structural element in the ceruloplasmin mRNA 3' untranslated region. Mol. Cell. Biol. 23: 1509-1519.
Mazumder, B., Sampath, P., Seshadri, V., Maitra, R. K., DiCorleto, P. E., and Fox, P. L. (2003) Regulated release of L13a from the 60S ribosomal subunit as a mechanism of transcript-specific translational control. Cell 115, 187-198.