Ravindra N Singh
- PhD, Biochemistry, 1993, Institute of Biochemistry and Physiology of Microorganisms, Russian Academy of Sciences, Pushchino, Russia
- MSc, Biochemistry, 1985, Banaras Hindu University, Varanasi, India
- BSc, Chemistry Honors, 1983, Banaras Hindu University, Varanasi, India
- Present Instructor-in-charge, BMS 575, Cellular and Molecular Biology
Singh group works on the interface of fundamental and translational biology. General interest of his group has been to understand the mechanism of alternative splicing, a vital process that increases the coding potential of genome in all higher eukaryotes. Alternative splicing is also associated with a growing number of diseases including neurological and neuromuscular disorders, cardiovascular disorders and cancer. Particular focus of his group has been to understand the molecular basis of Spinal Muscular Atrophy (SMA), a debilitating genetic disease of infants and children. His award-winning discovery relates to finding a unique regulatory element located within the non-coding region (or intron) of Survival Motor Neuron (SMN) gene. He has termed this novel regulatory element as “Intronic Splicing Silencer N1”, which is abbreviated as “ISS-N1” (US patent # 7,838,657). ISS-N1 remains the most studied antisense target for splicing correction in a human genetic disease. US Food and Drug Administration (FDA) has recently approved Spinraza (synonyms: Nusinersen, IONIS-SMNRX, ISIS-SMNRX), an antisense drug based on ISS-N1 target (Read the story). Hence, Spinraza becomes the first antisense drug to restore a full-length functional protein in a human disease (watch a video on YouTube).
Singh group continues to develop additional targets and antisense formulations for an efficient correction of aberrant splicing in SMA (see news links below). In a paradigm shifting discovery, Singh lab has recently reported a unique RNA structure formed by a deep intronic sequence as a regulator of SMA gene splicing (Slide Presentation). This discovery provides lead for developing yet another oligonucleotide-based therapy of SMA.
In addition to above accomplishments, Singh lab has made seminal contribution towards a better understanding of role of RNA binding proteins in regulation of splicing of SMN2 exon 7, skipping of which is intimately linked to SMA pathogenesis. His discoveries are relevant for uncovering the novel mechanisms of genome-wide regulation of alternative splicing in normal and pathological conditions. His other interests include RNA-protein interactions and isolation of RNA aptamers as detection and diagnostic tools.
Current funding source: National Institutes of Health (NIH) and Salsbury Endowment
News Links about Dr. Ravindra Singh:
- At a UMass lab, a eureka moment
- Iowa State University scientists locate possible therapy target for spinal muscular atrophy
- Iowa State University researchers link 'housekeeping' gene with male infertility
- ISIS begins recruting for Phase III clinical trial
- New Biotechnology Council Named
- Fix the splicing defect, stop the disease
- Iowa State researchers explore new treatments for a leading genetic cause of infants death
- Discovery of small antisense target for possible treatment of SMA
- Presidential early career award for scientists and Engineers (PECASE) from The White House
- 2006 Presidential Early Career Award for Scientists and Engineers (PECASE) (The highest civilian award given to young US scientists) Website
- Named Endowed Dr. John G. and Mrs. Doris Salsbury Chair (2008-2016)
- Permanent member of NIH CDIN study section (2008-2012)
- Editorial Board Member: BBA-Gene Regulatory Mechanisms, Frontiers in Bioscience, PLoS One, Scientific Reports (Nature)
- Organizing committee member, 2010 RNA in Motion Symposium, Ames IA, USA.
- Organizing committee member, 2010 One Health Symposium, Ames IA, USA.
- Active member of George Washington Carver internship program for disadvantaged students. Website
- Founding member and Co-Chair, 2012 Faculty Research Symposium, College of Veterinary Medicine, Iowa State University, Ames IA, USA.
- Member, Organizing committee, 2013 Faculty Research Symposium, College of Veterinary Medicine, Iowa State University, Ames IA, USA.
- Reviewer for many granting agencies including National Institutes of Health (NIH), National Science Foundation (NSF), US Department of Defense (DoD), Alzheimer's association, Italian Telethon Grants, Consiglio Nazionale delle Ricerche (CNR) Italy, Scottish Hospital Endowments Research Trust Grants, Medical Research Council (MRC) UK, National Medical Research Council (NMRC) Singapore, and US-Israel Binational Science Foundation.
- Reviewer for many journals including Annals of Human Genetics, Biochimica et Biophysica Acta, Clinica Chimica Acta, Current Molecular Medicine, Drug News & Perspectives, Expert Opinion in Drug discovery, FEBS Letters, Human Molecular Genetics, Human Genetics, Journal of Molecular Medicine, Journal of Cell Biology, Journal of Molecular Biology, Medical Science Monitor, Nature series journals, Neurology India, Nucleic Acids Research, PLoS series journals, Proceedings of National Academy of Sciences (USA), Science Translational Medicine, Trends in Molecular Medicine.
- American Society for Microbiology (ASM)
- The Genetics Society of America (GSA)
- The RNA Society
- Society for Neuroscience (SfN)
- American Association for Advancement of Science (AAAS)
- American Society for Human Genetics (ASHG)
- American Society for Cell Biology (ASCB)
- Oligonucleotide Therapeutic Society (OTS)
- Osborne Club, Iowa State University
- Ottesen EW, Seo J, Singh NN, Singh RN. (2017) A multilayered control of the human survival motor neuron gene expression by Alu elements. Front Microbiol. doi: 10.3389/fmicb.2017.02252 Pubmed.
- Singh NN, Del Rio-Malewski JB, Luo D, Howell MD, Singh RN. (2017) Activation of a cryptic 5' splice site reverses the impact of pathogenic splice site mutations in the spinal muscular atrophy gene. Nucleic Acids Res. doi: 10.1093/nar/gkx824j Pubmed.
- Howell MD, Ottesen EW, Singh NN, Anderson RL, Seo J, Sivanesan S, Whitley EM, Singh RN. (2017) TIA1 is a gender-specific disease modifier of a mild mouse model of spinal muscular atrophy. Sci Rep. 7(1):7183. doi: 10.1038/s41598-017-07468-2 Pubmed.
- Singh NN, Howell MD, Androphy EJ, Singh RN. (2017) How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy. Gene Ther. 24(9):520-526. doi: 10.1038/gt.2017.34 Pubmed.
- Howell MD, Ottesen EW, Singh NN, Anderson RL, Singh RN. (2017) Gender-specific amelioration of SMA Phenotype upon disruption of a deep intronic structure by an oligonucleotide. Mol Ther. doi: 10.1016/j.ymthe.2017.03.036 Pubmed.
- Singh RN, Howell MD, Ottesen EW, Singh NN. (2017) Diverse role of survival motor neuron protein. Biochim Biophys Acta. 1860(3), 299-315. Pubmed.
- Seo J, Singh NN, Ottesen EW, Lee BM, Singh RN. (2016) A novel human-specific splice isoform alters the critical C-terminus of Survival Motor Neuron protein. Sci Rep. 6:30778. Pubmed.
- Seo J, Singh NN, Ottesen EW, Sivanesan S, Shishimorova M, Singh RN. (2016) Oxidative Stress Triggers Body-Wide Skipping of Multiple Exons of the Spinal Muscular Atrophy Gene. PLoS One. 11(4):e0154390. doi: 10.1371/journal.pone.0154390. eCollection 2016. Pubmed.
- Ottesen EW, Howell MD, Singh NN, Seo J, Whitley EM, Singh RN. (2016) Sci Rep. 6:20193. doi: 10.1038/srep20193. Pubmed.
- Singh NN, Lee BM, DiDonato CJ and Singh RN (2015) Mechanistic principles of antisense targets for the treatment of spinal muscular atrophy. Future Medicinal Chemistry, 7, 1793-1808, Pubmed.
- Singh NN, Lee BM and Singh RN (2015) Splicing regulation in spinal muscular atrophy by RNA structure formed by long-distance interactions. Annanls of New York Academy of Sciences, 1341, 176-187, Pubmed, Pdf, Google citations.
- Howell MD, Singh NN and Singh RN (2014) Adances in therapeutic development for spinal muscular atrophy. Future Medicinal Chemistry, 6, 1081-1099, Pubmed, pdf, Google citations.
- Keil LM, Seo J, Howell MD, Hsu WH, Singh RN and DiDonato CJ (2014) A short antisense oligonucleotide ameliorates sumptoms of severe mouse models of spinal muscular atrophy. Molecular Therapy-Nucleic Acids, 3, e174, PubMed, Pdf, Google citations
- Seo J, Ottesen EW and Singh RN (2014) Antisense methods to modulate pre-mRNA splicing. Methods in Molecular Biology, 1126, 271-283, PubMed, Pdf.
- Singh NN, Lawler MN, Ottesen EW, Upreti D, Kaczynski JR and Singh RN (2013) An intronic structure enabled by a long-distance interaction serves as a novel target for splicing correction in spinal muscular atrophy. Nucleic Acids Research, 41, 8144-8165. PubMed, Pdf, Slide Presentation, Google citations
- Seo J, Howell MD, Singh NN and Singh RN (2013) Spinal Muscular Atrophy-An update on therapeutic progress. BBA-Molecular Basis of disease, 1832, 2180-2190, PubMed, Pdf, Google citation
- Sivanesan S, Howell MD, DiDonato CJ and Singh RN (2013) Antisense oligonucleotide mediated therapy of spinal muscular atrophy. Translational Neuroscience, 4, 1-7. Post-print pdf, Google citations
- Singh NN, Joonbae Seo, Sarah J Rahn and Singh RN (2012) A multi-exon-skipping detection assay reveals surprising diversity of splice isoforms of spinal muscular atrophy genes. PLOS ONE, 7, e49595. PubMed, Pdf, Google citations
- Singh NN and Singh RN (2011) Alternative splicing in spinal muscular atrophy underscores the role of an intron definition model. RNA Biology, 8, 935-954. PubMed, pdf, Google citations
- Singh NN, Seo J, Ottesen EW, Shshimorova M, Bhattacharya D and Singh RN (2011) TIA1 prevents skipping of a critical exon associated with spinal muscular atrophy. Molecular and Cellular Biology, 31, 935-954. PubMed, pdf, Google citations
- Singh NN, Hollinger K, Bhattacharya D and Singh RN (2010) Antisense microwalk reveals critical role of an intronic position linked to a unique long-distance interaction in pre-mRNA splicing. RNA, 16, 1167-1181. PubMed, pdf, Google citations
- Singh NN, Shishimorova M, Cao LC, Gangwani L and Singh RN (2009) A short antisense oligonucleotide masking a unique intronic motif prevents skipping of a critical exon in spinal muscular atrophy. RNA Biology, 6, 341-350. PubMed, pdf, Google citations
- Papp LV, Wang J, Kennedy D, Boucher D, Zhang Y, Gladyshev VN, Singh RN and Khanna KK (2008) Functional characterization of alternatively spliced human SECISBP2 transcript variants. Nucleic Acids Research, 36, 7192-206. PubMed, pdf, Google citations
- Singh RN(2007) Evolving concepts on human SMN pre-mRNA splicing. RNA Biology, 4, 7-10. PubMed, pdf, Google citations
- Singh NN, Singh RN and Androphy EJ (2007) Modulating role of a RNA structure in skipping of a critical exon in the spinal muscular atrophy genes. Nucleic Acids Research, 35, 371-389. PubMed, pdf, Google citations
- Singh NK, Singh NN, Androphy EJ and Singh RN (2006) Splicing of a Critical Exon of Survival Motor Neuron genes is regulated by a human-specific silencer element located in the last intron. Molecular and Cellular Biology, 26, 1333-1346. PubMed, pdf, Google citations
- Singh NN, Androphy EJ and Singh RN (2004) In vivo selection reveals features of combinatorial control that defines a critical exon in the spinal muscular atrophy genes. RNA, 10, 1291-1305. PubMed, pdf, Google citations
- Singh NN, Androphy EJ and Singh RN (2004) Regulation and regulatory activities of alternative splicing of the SMN genes. Critical Reviews in Eukaryotic Gene Expression, 14, 271-285. PubMed, Google citations
- Singh NN, Androphy EJ and Singh RN. (2004) An extended inhibitory context causes skipping of exon 7 of SMN2 in spinal muscular atrophy. Biochemical and Biophysical Research Communications, 315, 381-388. PubMed, Google citations
- Singh RN, Saldanha R, D’Souza LM and Lambowitz AM (2002) Binding of a group II intron-encoded reverse transcriptase/maturase to its high affinity intron RNA binding site involves sequence-specific recognition and autoregulates translation. Journal of Molecular Biology, 318, 287-303. PubMed, Google citations
- Wank H, SanFilippo J, Singh RN, Matsuuara M and Lambowitz AM (1999) A reverse transcriptase/maturase promotes RNA splicing by binding at its own coding segment in a group II intron. Molecular Cell, 4. 239-250. PubMed, Google citations
- Singh RN and Dreher TW (1998) Specific site selection in RNA resulting from a combination of nonspecific secondary structure and -CCR- boxes: initiation of minus strand synthesis by turnip yellow mosaic virus RNA-dependent RNA polymerase. RNA, 4, 1083-1095. PubMed, Google citations
Summer Scholar Projects:
Summer scholars (undergraduate and veterinary students) selected through various internship programs would learn one or more of the following techniques:
1. Blast analysis of alternative splicing of different genes using public data base
2. Isolation and processing of RNA from pathological samples (human and animal samples)
3. Design and perform PCR experiments to amplify alternatively spliced transcripts
4. Run agarose and polyacrylamide gel electrophoresis
5. Perform tissue culture experiments
6. Perform gene silencing experiments
7. Perform cloning and expression experiments
8. Perform protein isolation and purification
9. Perform immunological tests
10. Write and present scientific report
Prospective graduate students in Singh Lab
If you are interested in obtaining your Ph.D. in Singh laboratory, please apply to one or more of the following interdisciplinary graduate programs at Iowa State University:
Depending upon the availability of funds, each program selects a limited number of promising graduate students with the first-year stipend. First year students are given opportunity to rotate in three laboratories of their choice. If you are admitted to any of the above-mentioned programs and have interest in RNA Biology and/or genetic diseases, you are welcome to rotate in Singh laboratory. Singh laboratory has funds to support a limited number of talented Ph.D. candidates from the second year onward if students have demonstrated acceptable performance and creative potential during the rotation period. Please note that Singh laboratory does not accept students without a rotation. Should you have a question regarding any specific graduate program at Iowa State University, please contact the respective program coordinator through the specific weblink listed above.