The Corey Laboratory is interested in a wide spectrum of projects at the interface of chemistry and biology. Our primary focus is the study of how nucleic acids and nucleic acid mimics recognize target molecules inside cells. Our goal is to develop new strategies for manipulating gene expression that will 1) provide insights into important natural processes, 2) facilitate laboratory research, and 3) lay the foundation for drug development.
Project Areas include
Mechanism of Promoter-Targeted Antigene RNAs (agRNAs). The Corey Laboratory has observed that duplex RNAs can target sequences within gene promoters and either repress or activate gene expression in culture human cancer cells. These studies suggest that double-stranded RNA can recognize sequences within chromosomal DNA and that RNA-mediated control of gene expression is even richer than had been previously imagined.
Current research projects include; 1) Investigating the molecular mechanism of activating and repressing agRNAs 2) Searching for naturally occurring agRNAs 3) Studying the effect of chemical modifications on agRNA activity
Recognition of RNA and DNA by Peptide Nucleic Acids (PNAs) and Locked Nucleic Acids (LNAs). LNAs and PNAs are powerful tools for complementary hybridization. They bind complementary sequences with high specificity and high affinity.
Current research projects include; 1) Investigation of the mechanism of promoter-targeted LNAs and PNAs 2) Optimization of intracellular deliver of PNAs
Inhibition of of Expression of Huntingtin Protein Expression of mutant huntingtin causes Huntington?s disease, a devastating neurological disorder. The gene encoding mutant huntingtin is characterized by expanded numbers of the nucleotide triplet CAG. Our hypothesis is that chemically modified nucleic acids will be able to efficiently inhibit expression of huntingtin and possibly discriminate between the mutant and wild-type variants. We are currently testing PNA, agRNA, and siRNA inhibitors of huntingtin expression.
RESEARCH INTERESTS
Nucleic acids
Telomerase
antigene oligonucleotides
RNAi
antisense oligonucleotides
RECENT PUBLICATIONS
Schwartz, J. C., Younger, S. T., Nguyen, N-B., Hardy, D. B., Corey, D. R., and Janowski, B. A., "Antisense transcripts are targets for small activating RNAs" Nature Structural and Molecular Biology, 8/15:842-849, Summer 2008
Janowski, B. A., Kaihatsu, K., Huffman, K. E., Schwartz, J. C., Ram, R., Hardy, D., Mendelson, C. R., and Corey D. R., "Inhibiting transcription of chromosomal DNA using antigene peptide nucleic acids" Nature Chemical Biology, 1:210-215, September 2005
Janowski, B. A., Huffman, K. E., Schwartz, J. C., Ram, R., Hardy, D., Shames, D. S., Minna, J. D., and Corey D. R., "Inhibiting gene expression at transcription start sites in chromosomal DNA by antigene RNAs" Nature Chemical Biology, 1:216-222, September 2005
Janowski, B. A., Huffman, K. E., Schwartz, J. C., Ram, R., Nordsell, R., Shames, D. S., Minna, J. D., and Corey, D. R., "Involvement of Ago1 and Ago2 in mammalian transcriptional silencing" Nature Stuctural and Molecular Biology, 13:787-792, 2006
Janowski, B. A., Younger, S. T., Hardy, D. B., Ram, R., Huffman, K. E., and Corey, D. R., "Activating gene expression in mammalian cells with promoter-targeted duplex RNAs" Nature Chemical Biology, 3:166-173, 2007
Schwartz, J. C., Younger, S. T., Nguyen, N-B., Hardy, D. B., Corey, D. R., and Janowski, B. A., "Antisense transcripts are targets for small activating RNAs" Nature Structural and Molecular Biology, 8/15:842-849, Summer 2008
SIGNIFICANT PUBLICATIONS
Liu, Y., Braasch, D. A., Nulf, C. J., and Corey, D. R., "Isoform-specific inhibition of cellular gene expression by peptide nucleic acid" Biochemistry, 43:1921-1927, 2004
Norton, J. C., Piatyszek, M. A., Wright, W. E., Shay, J. W., Corey, D. R, "Inhibition of human telomerase activity by peptide nucleic acids" Nature Biotech., 14:615-620, 1996
Herbert, B-S., Pitts, A. E., Baker, S. I., Hamilton, S. E., Wright, W. E., Shay, J. W. and Corey, D. R., "Inhibition of telomerase leads to eroded telomeres, reduced proliferation, and cell death" Proc. Natl. Acad. Sci. USA, 96:14726-14781, 1999
Hu, J. and Corey, D. R., "Inhibiting Gene Expression with PNA-Peptide Conjugates that Target Chromosomal DNA" Biochemistry, 46:7581-7589, 2007
Janowski, B. A., Hu, J., and Corey, D. R., "Antigene inhibition by peptide nucleic acids and duplex RNAs" Nature Protocols, 1:436-433, 2006
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