Claes Wahlestedt, MD, Ph.D.
Professor, Molecular Therapeutics, TSRI
Adjunct Professor, Molecular and Integrative Neurosciences, TSRI
M.D., University of Lund, Sweden, 1984
Ph.D. in Pharmacology, University of Lund, Sweden, 1987
Department of Molecular Therapeutics
Department of Neuroscience
The Scripps Research Institute
130 Scripps Way C347
Jupiter, Florida 33458
Most likely conventional protein-coding genes account for only a minority of human RNA transcripts. A substantial component of the full-length mouse and human cDNA sets that we and others have analyzed does not contain an annotated protein-coding sequence and most likely corresponds to noncoding RNA. Many of the noncoding sequences constitute natural antisense RNA transcripts. We have shown that the majority of noncoding RNAs identified to date have substantial conservation across species. Moreover, we have shown that many noncoding RNA and antisense transcripts have differential expression under various conditions and can affect conventional gene expression.
RNA interference has become one of the most important gene manipulation technologies. Short interfering RNA, the inducer of RNA interference in mammals, can be used to elucidate gene functions by rapidly silencing expression of a target gene. Today, short interfering RNAs are widely used as research tools and have potential for becoming therapeutic agents. We have built a portfolio of short interfering RNA technology. In this package we have a powerful short interfering RNA vector system, a validation system, and a design system, all of which are unique. Combining these technologies with the high-throughput chemistry for on-chip DNA synthesis, we have set up a system for constructing short interfering RNAs. Finally, we have also introduced the use of locked nucleic acids in short interfering RNAs and have shown a range of beneficial properties of these agents.
More than half of known drugs bind to G protein-coupled receptors (GPCRs). We have continued our long-standing work on GPCRs, particularly certain neuropeptide receptors. At Scripps Florida, these efforts are forming part of the drug discovery program. Moreover, during the past year, we published on our human GPCR database, which contains polymorphism data, that is, data that point to interindividual differences in GPCR sequences. Information on polymorphisms may be increasingly important in drug discovery and development efforts.
We are pursuing drug discovery related to several human disorders that affect the brain. Our goal is to identify biomarkers that are associated with such common disorders. We wish to understand what makes certain individuals susceptible and how their responses to drug treatment may differ (pharmacogenomics). We are involved in genotyping DNA from patients with major depression, alcoholism, diabetes, obesity, Alzheimer's disease, Parkinson's disease, and attention deficit/hyperactivity disorder.
Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE Finch CE, Kenny PJ, Wahlestedt C. Expression of noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase expression. Nature Medicine 14:723-30, 2008. PMID: 18587408
Shan G, Li Y, Zhang J, Li W, Szulwach KE, Duan R, Faghihi MA, Khalil AM, Lu L, Paroo Z, Chan AW, Shi Z, Liu Q, Wahlestedt C, He C, Jin P. A small molecule enhances RNA interference and promotes microRNA processing. Nature Biotechnology 26(8):933-40, 2008. PMID: 18641635
Kocerha J, Faghihi MA, Lopez-Toledano MA, Huang J, Ramsey AJ, Caron MC, Sales N, Willoughby DA, Elmen J, Hansen HF, Orum H, Kauppinen S, Kenny and Wahlestedt C. MicroRNA-219 modulates NMDA receptor mediated neurobehavioral dysfunction. Proc Natl Acad Sci (USA), 106(9):3507-12, 2009. PMID: 19196972
Khalil AM, Faghihi MA, Modarresi F, Brothers SP, Wahlestedt C. A novel noncoding RNA transcript with antiapoptotic function is silenced in Fragile X Syndrome. PLoS ONE, doi/pone.0001486, 2008. PMID: 18213394
St-Laurent III G., Wahlestedt C. Noncoding RNAs: Couplers of analog and digital information in nervous system function? Trends in Neurosciences 30: 612-21, 2007. PMID: 17996312
Carninci P*, Wahlestedt C*, et al. Genome-wide analysis of mammalian promoter architecture and evolution. Nature Genetics 38, 626-635. 2006. (*Core contributors) PMID: 16645617
Katayama S, Tomary T, Kasukawa T, Waki K, Suzuki M, Nishida H, Kawai J, Suzuki H, Carninci P, Hayashizaki Y, Wells C, Frith M, Ravasi T, Pang K, Mattick J, Hume D, Lipovich L, Engstrom PG, Mizuno Y, Faghihi MA, Sandelin A, Chalk A, Mottagui-Tabar S, Lenhard B, Wahlestedt C. Antisense transcription in the mammalian transcriptome. Science 309:1564-1566, 2005. PMID: 16141073
Carninci P*, Wahlestedt C*, et al. The transcriptional landscape of the mammalian genome. Science 309: 1559-1563, 2005. (*Core contributors). PMID: 16141072
Okazaki Y*, Wahlestedt C*, et al. Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature 420:563-573, 2002. (*Core contributors) PMID: 12466851
Wahlestedt C, Salmi P, Good L, Kela J, Johnsson T, Hökfelt T, Broberger C, Porreca F, Lai J, Ren K, Ossipov M, Koshkin A, Jakobsen N, Skouv J, Ørum H, Jacobsen MH, Wengel J. Potent and nontoxic antisense oligonucleotides containing locked nucleic acids. Proc Natl Acad Sci (USA) 97: 5633-5638, 2000. PMID: 10805816
Awards, Recognition, Appointments, and Honors
Fantom consortium (transcriptomics)
Member of review committees in several countries
Organizer of Nobel Conferences