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Oregon State University College of Veterinary Medicine eNewsletter

Research Profile-Dr. Patrick Chappell

March 15th, 2010
Dr. Patrick Chappell

Dr. Patrick Chappell

Dr. Patrick Chappell is currently an assistant professor in the Department of Biomedical Sciences at the College of Veterinary Medicine. From 2006 until 2009, he was a research assistant professor in the Department of Zoology at OSU. He received his bachelor’s degree in psychology from Emory University in Atlanta, Ga. and his Ph.D. in neuroscience from the Northwestern University Institute for Neuroscience in Chicago, Ill. He completed his dissertation work on the role of hypothalamic progesterone receptors in the generation of preovulatory surges in female rodents. Dr. Chappell performed his postdoctoral work in the Department of Reproductive Medicine at the University of California in San Diego, California where he received a National Research Service Award and Mentored Career Fellowship from the National Institutes of Health.

GnRH (green) co-localized with the circadian clock protein BMAL1 (red) in a coronal slice of mouse hypothalamus.

GnRH (green) co-localized with the circadian clock protein BMAL1 (red) in a coronal slice of mouse hypothalamus.

Dr. Chappell’s laboratory predominantly investigates the role of endogenous intracellular circadian clocks in the neuroendocrine regulation of reproduction in mammals. Using a combination of molecular biological and physiological techniques, they are exploring how oscillatory gene expression patterns in hypothalamic gonadotropin-releasing hormone (GnRH) neurons modulate secretion of this neuropeptide, which is crucial for gamete production, steroid hormone production, and ovulation in females. GnRH stimulates the anterior pituitary to secrete the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are required for gametogenesis and steroidogenesis in the testes and ovaries. GnRH release patterns vary from episodic pulses that occur every 30-60 minutes to dramatic surges that initiate ovulation in females. Interestingly, ovarian estrogen acts as both a negative feedback inhibitor of GnRH release during the early follicular and luteal phases and a positive feedback stimulation of GnRH release just prior to ovulation. They are exploring how this steroid hormone may perform this dual role by interacting with endogenous transcriptional oscillators within GnRH neurons and within other hypothalamic neuronal populations. The lab utilizes several models of molecular circadian clock disruption, and is determining the necessity of cell-specific clocks using multiple transgenic mouse lines. Additionally, they have created several sub-cloned immortalized cultured GnRH-secreting neuronal cell lines in which they can monitor clock oscillations concomitantly with peptide secretion, and in which they can reversibly disrupt clock function. Specific projects available include examining the effects of estrogen feedback on GnRH neuronal gene expression patterns, activity, and secretion, using both in vitro cell culture and in vivo mouse models. These studies will provide insight into broad mechanisms of endocrine neurosecretion, and advance circadian biology by exploring how transcriptional oscillations can control synchronous multi-cellular events to regulate numerous biological processes and even orchestrate complex behaviors. Potential applications of this research include new directions in treating a range of reproductive physiological disorders that result from malfunction of hypothalamic neurosecretion, including polycystic ovarian syndrome (PCOS) and primary ideopathic hypogonadism, both of which are associated with atypical hormone release patterns.

The Chappell lab has also opened a new line of investigation into the role of clock gene expression patterns in the initiation and progression of hormone-responsive reproductive cancers, such as prostate and breast cancer. A recent publication from their group demonstrated that healthy murine prostate epithelial cells exhibit robust oscillations of circadian clock genes, and they have recently determined that cancerous cells lack these rhythms. The lab is exploring the possibility that clock dysregulation may represent one etiology of cancer in these cells, particularly in the transition to a hormone-refractory state, and is investigating physical interactions between circadian clock components, the androgen receptor, and modulators of chromatin remodeling. This research could provide insight into novel chronotherapeutic treatments of reproductive cancers, by determining how endogenous clocks interact with cell cycle regulators and steroid hormone receptors, and how these inherent timing mechanisms may be involved in determining whether prostate epithelial cells progress toward either apoptosis or proliferation. His lab utilizes methodologies ranging from real-time quantitative RT-PCR, transient transfection of cultured cells, evaluation of xenografted tumors in mice, and monitoring gene expression and protein abundance changes in cells using fluorescence microscopy and luminometry.

GnRH secretion profile of perifused GT1-7 cells.

GnRH secretion profile of perifused GT1-7 cells.

Immortalized GnRH-secreting GT1-7 cells.

Immortalized GnRH-secreting GT1-7 cells.

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