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Thomas Jefferson University - Diane E. Merry, Ph.D.
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Diane E. Merry, Ph.D.
Biochemistry and Molecular Biology
Thomas Jefferson University
Jefferson Medical College
Department of Biochemistry & Molecular Biology
Associate Professor
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Mailing Address
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233 South 10th Street, 208 BLSB
Philadelphia, Pennsylvania 19107
United States
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Expertise and Research Interests
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The research in my lab centers on understanding the molecular pathways by which motor neurons become dysfunctional in response to expression of polyglutamine-expanded androgen receptor in the neurodegenerative disease spinal and bulbar muscular atrophy. In a more general sense, these studies are designed to understand how neurons respond to the accumulation of misfolded proteins. Thus, much of the research in my lab is disease-driven basic research. A small area of research (points 6 and 7) is translational. The areas of investigation follow:
1. Why do nuclear neuronal proteasomes fail to efficiently process expanded polyglutamine-containing proteins? How does the cellular stress response, or the lack thereof, factor into neuronal dysfunction in response to expanded polyglutamines?
2. How is the degradation of the androgen receptor regulated? Unlike the other steroid hormone receptors, the AR is stabilized by hormone binding; what controls this stabilization, and how is its ultimate degradation regulated? What roles do nuclear import, nuclear export, DNA binding, and phosphorylation play in the regulation or AR catabolism?
3. What drives the motor neuron specificity of expanded-polyglutamine androgen receptor toxicity? Does the motor neuron expression of 5 alpha-reductase, which produces the most potent androgen, dihydrotestosterone, confer susceptibility?
4. We have found reductions in the level of neurofilament heavy chain within motor neurons of diseased transgenic mice; this reduction is reversed by surgical castration. Does this molecular alteration result in alterations in axonal trafficking, leading to a loss of trophic support, and/or alterations at the neuromuscular juntion?
5. Markers of cellular senescence are induced in motor neurons of our diseased transgenic mice. Studies are underway to determine if the neuronal dysfunction in this disease is a result of premature initiation of a program of cellular senescence.
6. Our finding that molecular chaperones promote the turnover of the mutant expanded polyglutamine androgen receptor suggests a therapeutic avenue. We have performed a high-throughput drug screen and identified several FDA-approved drugs that mimic the effect of molecular chaperones on steady-state polyglutamine-expanded AR levels. Studies are ongoing to further define the mechanism of action of these drugs and to perform pre-clinical testing on our transgenic mouse model.
7. We are developing gene therapeutic approaches to the delivery of the molecular chaperones Hsp70 and Hsp40 to the nervous system, using lentiviral vectors.
Laboratory Staff
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Publications
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- Kobayashi, Y., Miwa, S., Merry, D. E., Kume, A., Mei, L., Doyu, M., and Sobue, G.: Caspase-3 cleaves the expanded androgen receptor protein of spinal and bulbar muscular atrophy in a polyglutamine repeat length-dependent manner. BBRC 252:145-150, 1998.
- Nakamura, M., Raghupathi, R., Merry, D. E., Scherbel, U., Saatman, K. E., and McIntosh, T. K.: Overexpression of bcl-2 is neuroprotective after experimental brain injury in transgenic mice. J. Comp. Neurol. 412:681-692, 1999.
- McCampbell, A., Taylor, J. P., Taye, A. A., Robitschek, J., Li, M., Walcott, J., Merry, D., Chai, Y., Paulson, H., Sobue, G., Fischbeck, K. H.: CBP sequestration by expanded polyglutamine-containing protein. Hum. Molec. Genet. 9:2197-2202, 2000.
- Abel, A., Walcott, J., Woods, J., Duda, J., and Merry, D. E.: Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice. Hum. Molec. Genet. 10:107-116, 2001.
- Bailey, C. K., Andriola, I. F. M., Kampinga, H. H., and Merry, D. E.: Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy. Hum. Molec. Genet., 11:515-523, 2002.
- Luthi-Carter, R., Strand, A. D., Hanson, S. A., Kooperberg, C., Schilling, G., La Spada, A. R., Merry, D. E., Young, A. B., Ross, C. A., Borchelt, D. R., and Olson, J. M.: Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington's disease mouse models reveal context-independent effects. Hum. Molec. Genet. 11:1927-1937, 2002.
- Chan, H. Y. E., Warrick, J. M., Andriola, I., Merry, D. E., and Bonini, N. M.: Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum. Molec. Genet. 11:2895-2904, 2002.
- Walcott, J. L. and Merry, D. E.: Ligand promotes intranuclear inclusions in a novel cell model of spinal and bulbar muscular atrophy. J. Biol. Chem. 277:50855-50859, 2002.
- Mandrusiak, L. M., Beitel, L. K., Wang, X. l., Scanlon, T. C., Merry, D. E., and Trifiro, M. A.: Transglutaminase potentiates ligand-dependent proteasome dysfunction induced by polyglutamine-expanded androgen receptor. Hum. Molec. Genet. 12:1497-1506, 2003.
- Chevalier-Larsen, E.S., O'Brien, C.J., Wang, H., Jenkins, S.C., Holder, L., Lieberman, A.P., and Merry, D.E.: Castration restores function to aged symptomatic males in a transgenic mouse model of SBMA. 2003, Submitted.
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Individual Expertise profile of
Diane E. Merry, Ph.D., Copyright © Diane E. Merry, Ph.D..
Last Updated
by Admin
: Monday, August 25, 2008 12:03:56 PM
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