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CHANDLER LABORATORY
Our lab is interested in the regulation of pre-mRNA splicing and how disruption of this regulation can lead to pediatric diseases such as cancer. Current work in our lab elucidates alternative splicing as a novel mechanism by which cellular injury can control the activity of p53 and how changes in the regulation of splicing can lead to tumorigenesis. The transcription factor p53 is known to induce G1 arrest of the cell cycle and/or apoptosis. MDM2 is one of the most critical regulators of p53. Using in vitro biochemical assays and genetically engineered mouse models we are currently investigating differential RNA splicing of both the MDM2 and p53 pre-mRNAs and investigating the roles of each in normal cell function as well as disease.
Another pediatric disease Proximal Spinal Muscular Atrophy (SMA), the leading genetic cause of infant mortality in humans, is in part due to a mutation that affects splicing of a duplicated gene that controls neuronal growth (SMN2). We are interested in generating viable mouse models for human SMA with the long-term goal of testing candidate therapies that target the human SMN2 gene. To do this, we are generating mouse lines that will be utilized to answer many questions pertaining the therapeutic possibilities of SMN replacement, splicing correction by drug or antisense treatment, and the correct timing of such therapies.
Our research represents a novel perspective in pediatric research that highlights the role of perturbation of pre-mRNA processing in disease phenotypes. The increased awareness of regulated RNA processing and recent identification of several disease-causing mutations that affect splicing give rise to a new generation of potential therapeutic targets. Point mutations and the resultant splice variants may both be successfully targeted for therapeutic benefits in the future.
Web Site:: http://chandlerlab.nchresearch.org/
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| Education |
| 2004 |
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Postdoctoral Fellow |
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Cancer Genetics |
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M.D. Anderson Cancer Center, Houston, TX |
| 2002 |
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Postdoctoral Fellow |
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Human Genetics |
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M.D. Anderson Cancer Center, Houston, TX |
| 1998 |
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Ph.D. |
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Biomedical Sciences |
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University of Texas Health Science Center, Houston, TX |
| Selected Publications |
| Chandler, D.S. (2007). Regulation of p53 tumor suppressor activity by alternative splicing. Alternative Splicing in Cancer. (ed. J.P. Venables) Research Signposts Publishers. |
| Chandler, D.S., Singh, R.K., Caldwell, L.C., Bitler, J.L., and Lozano, G. Genotoxic stress induces coordinately regulated alternative splicing of the p53 modulators MDM2 and MDM4. Cancer Research, 66: 9502-9508, 2006. |
| Chandler, D.S., Lozano, G. Metastasis, Mouse Models of Human Cancer, 307-320,2004. (ed. Eric C. Holland) |
| Chandler, D.S., Qi, J., and Mattox, W. Direct repression of splicing by transformer-2. Molecular and Cellular Biology, 23(15): 5174-85, 2003. |
| Lott, S.T.*, Chandler, D.S.*, Curley, S., Foster, C.J., El-Naggar, A., Frazier, M., Lovell, M.M., Strong, L.C., Killary, A. M. High Frequency Loss of Heterozygosity in von Hippel-Lindau (VHL)-Associated and Sporadic Pancreatic Islet Cell Tumors: Evidence for a Stepwise Mechanism for Malignant Conversion in VHL Tumorigenesis. Cancer Research, 62: 1952-1955, 2002. *designates co-first authors |
| Chandler, D.S., McGuffin, M.E., Mattox, W. Functionally antagonistic sequences are required for normal autoregulation of Drosophila. tra-2 pre-mRNA splicing. Nucleic Acids Research, 29(14):3012-9, 2001. |
| McGuffin, M.E., Chandler, D.S., Somaiya, D., Dauwalder, B. and Mattox, W. (1998). Autoregulation of transformer-2 alternative splicing is necessary for normal male fertility in Drosophila. Genetics, 149: 1477-1486, 1998. |
| Chandler, D.S., McGuffin, M.E., Piskur, J., Yao, J., Baker, B.S., Mattox, W. Evolutionary conservation of germline specific autoregulation by the sex determination factor transformer-2. Molecular and Cellular Biology, 17: 2908-2919, 1997. |
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