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Ravindra N Singh

Ravindra Singh
Ravindra Singh

Ph.D.

Professor and Salsbury Chair
Biomedical Sciences
(515) 294-8505
2034 Vet Med
Expertise / Research Area

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. ISIS Pharmaceuticals has recently launched phase 2/3 clinical trial of ISS-N1-targeting drug ISIS-SMNRX. If successful, this will be the first antisense drug to restore a full-length functional protein in a human disease. 

 

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. 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:

 

 

 

Teaching

Instructor in charge of BMS 575 (Cellular and Molecular Biology)

Education

B. Sc.: Banaras Hindu University, India 1983
M. Sc.: Banaras Hindu University, India 1985
Ph.D.:  Russian Academy of Sciences, Russia, 1993.

Selected Publications

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, PubMedPdf.

Seo J, Ottesen EW and Singh RN (2014) Antisense methods to modulate pre-mRNA splicing. Methods in Molecular Biology, 1126, 271-283, PubMedPdf.

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

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

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

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

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

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. PubMedpdf

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. PubMedpdf

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

Singh RN(2007) Evolving concepts on human SMN pre-mRNA splicing. RNA Biology, 4, 7-10. PubMed, pdf

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

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

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

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

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

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

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

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

Leadership

  • 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.
  • Managing Editor of “Frontiers of Biosciences.”
  • Reviewed 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.
  • Reviewed 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), Trends in Molecular Medicine.

 

Honors & Awards
  1. 2006 Presidential Early Career Award for Scientists and Engineers (PECASE) (The highest civilian award given to young US scientists) Website

  2. Named Endowed Dr. John G. and Mrs. Doris Salsbury Chair (Since 2008)

  3. Permanent member of NIH CDIN study section (2008-2012)

Memberships

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

 

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:

Interdepartmental Genetics Program (IG)

Interdepartmental Molecular Cellular and Developmental Biology Program (MCDB)

Interdepartmental Neuroscience Program (Neuro)

Toxicology Graduate Program (Tox)

Bioinformatics and Computational Biology Graduate Program (BCB)


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. 

 

Postdoctoral position is open in Singh Lab 

(see advertisement in Science)

A post-doctoral position is available in Singh Lab for a motivated and talented fresh graduate with experience in RNA Biology, cell biology and/or Bioinformatics. This position is ideally suited for a candidate who is primarily trained in molecular and cell biology techniques including expression and characterization of microRNAs, long non-coding RNAs (lnc RNAs), mechanism of splicing,  RNA-protein interactions, RNA structure, confocal microscopy and sequence-based bioinformatics. Candidate with spinal muscular atrophy or RNA splicing background will get preference. Candidate should have proven record of publication as first author in a high-impact journal.  

 

Interested applicant should send full CV and names of three references to: singhr@iastate.edu