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3258 TAMU Office: Lab: Fax: 979-845-2891 |
Biography |
| Paul E. Hardin received his B.S. in Biology from Southern Methodist University in 1982 and his Ph.D. in Genetics from Indiana University in 1987. After investigating the Drosophila biological clock as a post-doctoral fellow with Dr. Michael Rosbash at Brandeis University, he joined the Biology Department at Texas A&M as an Assistant Professor in 1991. Dr. Hardin joined the Biology and Biochemistry Department at the University of Houston as an Associate Professor in 1995, was promoted to Professor in 2000, and was named a John and Rebecca Moores Professor in 2004. Dr. Hardin returned to Texas A&M in 2005 as a Professor in the Department of Biology and holder of the John. W. Lyons Jr. '59 Chair. | |
| Molecular Genetics of Biological Clocks | |
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Work in my laboratory focuses on understanding the molecular circuitry that underlies circadian clock function in the fruit fly, Drosophila melanogaster . Like other organisms, these flies display daily rhythms in molecular, physiological and behavioral events that are controlled by an innate, genetically encoded, circadian clock. Much of our work revolves around the period ( per ) , timeless ( tim ), cycle ( cyc ), Clock ( Clk ), PAR domain protein 1 epsilon ( Pdp1 e ) and vrille ( vri ) genes, which form the core of the circadian time keeping mechanism, or oscillator, in Drosophila . We previously found that the core mechanism underlying oscillator function in flies revolves around two interlocked feedback loops in gene expression. Subsequent studies showed that interlocked feedback loops are a conserved feature of the clock mechanism. The operation of these feedback loops is dependent on the heterodimeric bHLH-PAS transcription factors CLK and CYC, which bind E-box elements to activate the transcriptional feedback regulators vri , Pdp1 e , per and tim . VRI and PDP1 e proteins feedback to control the inhibition and subsequent activation of Clk transcription, respectively, while PER and TIM proteins feedback as a heterotrimeric complex with DBT kinase to inhibit CLK-CYC dependent transcription. These transcriptional regulatory events, along with post-translational control of protein accumulation, subcellular localization and degradation, maintain circadian cycles in gene expression that control rhythmic outputs. We are currently investigating transcriptional and post-transcriptional mechanisms that control when core feedback loop proteins function, with the ultimate goal of defining the molecular interactions that regulate the timing of events which make these feedback loops a circadian oscillator. In addition, we are identifying developmental factors that determine which cells will have circadian clocks. This feedback loop mechanism operates autonomously in many neuronal and non-neuronal tissues throughout the fly. However, little is known about the rhythms controlled by different cell-specific oscillators with the exception of locomotor activity, which is controlled by "lateral neurons" within the central brain. In collaboration with Dr. Stuart Dryer at the University of Houston, we discovered that olfactory responses are rhythmic. These rhythms, as measured by electroantennagrams (EAGs), continue in constant darkness, are dependent on per and tim, and are controlled by oscillators in peripheral tissues. We recently showed that circadian oscillators in antennal neurons are both necessary and sufficient to mediate olfaction rhythms, indicating that these cells act as independent circadian pacemakers. Our studies are now focused on determining what component of the olfactory system is controlled by the clock and what effect these rhythms have on behavior. |
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| Selected Publications | |
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Benito, J., H. Zheng, F. S. Ng and P. E. Hardin (2008) Transcriptional feedback loop regulation, function and ontogeny in Drosophila. Cold Spring Harbor Sym. Quant. Biol., in press. Bray, M.S., C. A. Shaw, M. W. Moore, R. A. Garcia, M. M. Zanquetta, D. J. Durgan, W. J. Jeong, J. Y. Tsai, H. Bugger, D. Zhang, A. Rohrwasser, J. H. Rennison, J. R. Dyck, S. E. Litwin, P. E. Hardin, C. W. Chow, M. P. Chandler, E. D. Abel, M. E. Young. (2008) Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression. Am J Physiol Heart Circ Physiol., 294, H1036-1047. Matsumoto, A., M. Ukai-Tadenuma, R. G. Yamada, J. Houl, K. D. Uno, T. Kasukawa, B. Dauwalder, T. Q. Ito, K. Takahashi, R. Ueda, P. E. Hardin, T. Tanimura and H. R. Ueda (2007) A functional genomics strategy reveals clockwork orange as a transcriptional regulator in the Drosophila circadian clock. Genes Dev. 21, 1687-1700. Kim, E. Y., H. W, Ko, W. Yu, P. E. Hardin and I. Edery (2007) A DOUBLETIME kinase binding domain on the Drosophila PERIOD protein is essential for its hyperphosphorylation, transcriptional repression and circadian clock function. Mol. Cell. Biol. 27, 5014-5028. Benito, J., H. Zheng and P. E. Hardin (2007) PDP1ε functions downstream of the circadian oscillator to mediate behavioral rhythms. J. Neurosci. 27, 2539-2547. Lazareva, A., W. Mattox, P. E. Hardin and B. Dauwalder (2007) A role for the adult fat body in Drosophila male courtship behavior. PLOS Genetics 3, e16. Yu, W., and P. E. Hardin (2007) Use of firefly luciferase assays to monitor circadian molecular rhythms in vivo. In Methods in Molecular Biology (E. Rosato, ed.) Humana Press, Inc., New Jersey, vol. 362, 465-480. Fujii, S., P. Krishnan, P. E. Hardin and H. Amrein (2007) Nocturnal male sex drive in Drosophila. Curr. Biol. 17, 244-251. Durgan, D.J, N. Trexler, O. Egbejimi, C.A. Shaw, M.S. Bray, P.E. Hardin, M.P. Chandler C.-W. Chow and M.E. Young (2006) The circadian clock within the cardiomyocyte modulates responsiveness of the heart to fatty acids. J. Biol. Chem. 281, 24254-24269. Yu, W., and P. E. Hardin (2006) Circadian Timekeeping Mechanisms in Animals. J. Cell Sci. 119, 4793-4795. Hardin, P. E. (2006) Essential and expendable features of the circadian timekeeping mechanism. Curr. Opin. in Neurobiol. 16, 686-692. Hardin, P. E., and W. Yu (2006) Circadian Transcription: Passing the HAT to CLOCK. Cell 125, 424-26. Yu, W., H. Zheng, J. H. Houl and P. E. Hardin (2006) PER dependent rhythms in CLK phosphorylation and E-box binding regulate circadian transcription. Genes Dev. 20, 723-733. Houl, J. H., W. Yu, S. M. Dudek and P. E. Hardin (2006) Drosophila CLOCK accumulates in nuclei of circadian oscillator cells and additional non-oscillator cells at all times of the daily cycle. J. Biol. Rhythms 21, 93-103. Hardin, P. E. (2005) The circadian timekeeping system of Drosophila . Curr. Biol., 15, R714-R722 Krishnan, P., S. E. Dryer and P. E. Hardin (2005) Measuring circadian rhythms in olfaction using electroantennograms. Methods Enzymol. 393, 495-508. Hardin, P. E. (2004) Transcription regulation within the circadian clock: The E-box and beyond. J. Biol. Rhythms 19, 348-360. Tanoue, S., P. Krishnan, B. Krishnan, S.E. Dryer and P.E. Hardin (2004) Circadian clocks in antennal neurons are required for olfaction rhythms in Drosophila . Curr. Biol. 14, 638-649. Glossop, N. R. J., J. H. Houl, H. Zheng, F. S. Ng, S. M. Dudek and P. E. Hardin (2003) VRI feeds back to control circadian transcription of Clock in the Drosophila circadian oscillator. Neuron 37, 249-261. Cyran, S.A., A.M. Buchsbaum, K.L. Reddy, M.-C. Lin, N.R.J. Glossop, P.E. Hardin, M.W. Young, R.V. Storti and J. Blau (2003) vrille , Pdp1 and dClock form a second feedback loop in the Drosophila circadian clock. Cell 112, 329-341. Kim, E.-Y., K. Bae, F. S. Ng, N. R. J. Glossop, P .E Hardin and I. Edery (2002) Drosophila CLOCK is under post-transcriptional control and influences light-induced activity. Neuron, 34, 69-81. Glossop, N.R.J. and P.E. Hardin (2002) Central and peripheral circadian oscillator mechanisms in flies and mammals. J. Cell Science 115, 3369-3377. Krishnan, B., J. D. Levine, K. Sisson, H. B. Dowse, P. Funes, J. C. Hall, P. E. Hardin and S. E. Dryer (2001) A novel role for cryptochrome in a Drosophila circadian oscillator. Nature 411, 313-317. |
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