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PH.D. University of Western Ontario |
Research in my laboratory is centered around the prevention and remediation of the catastrophic bone loss associated with osteoporosis, a condition which affects 35% of the post-menopausal female population. The laboratory focuses on basic science mechanisms, while a strong link with clinical research into osteoporosis and protein drug discovery is maintained. The laboratory is located at the Lawson Health Research Institute (Grosvenor Campus), a unique environment which fosters cooperation and collaboration among researchers in various disciplines. I am privileged to work in a team environment with Dr. Laurence Fraher (Vitamin D metabolism and immune function) and Dr. Tony Hodsman (Nephrology, Regional Osteoporosis Program) where each of us brings our unique skills together to apply our research from basic science to the clinical setting. Our lab works closely in the area of drug development with both the NRC and the osteoporosis clinical trials unit.
There are two main areas of interest to my laboratory research that have been funded by two consecutive CIHR grants.
1. First, bone development and growth is under the control of many hormones and humoral factors with parathyroid hormone (PTH) and PTH-related protein (PTHrP) being among the most important. The receptor for PTH/PTHrP, the PTHR, mediates the actions of the hormone within the bone environment. Recently, we have discovered that the PTHR not only signals through the traditional cAMP/PKA and PLC pathways, but that it is also translocated to the nucleus of target cells. At this time, we are using targeted mutagenesis of the PTHR and transfection into LLC-PK1 cells to uncover the mechanism of nuclear translocation of the PTHR and the involvement of ligand in this process. Upcoming Projects: (1) Does nuclear translocation of the PTHR play a role in discriminating the effect (catabolic vs. anabolic) of the hormone. (2) The direct, nuclear effects of the PTHR will be examined using proteomic and genomic technology.
2. Second, PTH/PTHrP can be both anabolic or catabolic to bone depending on the route of administration. Intermittent dosing of both rats and humans with PTH is anabolic and is now approved as a clinical therapy for osteoporosis. Using cultured osteoblastic bone cells, we are examining the role of dosing (continuous vs. intermittent) on the localization of the PTHR. We are also working on selectively anabolic PTH analogues. In collaboration with scientists at the NRC and Drs. Fraher and Hodsman, we have discovered that the PTH analogue, PTH 1-31 lactam, is highly anabolic in rats and in preliminary human studies appears not to cause hypercalcemia. We are undertaking the first stage clinical trial of this compound in healthy human volunteers in the next few months. We are exploring the effects of PTH 1-31 our cultured osteoblast model with respect to its ability to regulate OPG and RANKL, key molecules in osteoblast to osteoclast communication. Upcoming Projects: We are planning studies to determine the role of PTH and PTH 1-31 in the generation of second messengers and how this may relate to regulation of OPG and RANKL.
3. We have recently discovered that the osteoclast expresses the PTHR. In collaboration with Dr. Sims and Dr. Dixon (Dept. of Physiology, UWO) we are exploring the concept that osteoclasts can and do express the PTH receptor. Upcoming Projects: (1) Characterization of osteoclast PTH receptors. (2) Functional role of osteoclast PTH receptor.
Watson PH, Fraher LJ, Natale BV, Kisiel M, Hendy GN, Hodsman AB 2000 Nuclear localization of the type 1 PTH/PTHrP receptor in MC3T3-E1 cells: association with the cell cycle. Bone 26: 221-225 Watson PH, Fraher LJ, Hendy GN, Chung U-I, Kisiel M, Natale BV, Hodsman AB 2000 Nuclear localization of the type 1 PTH/PTHrP receptor in rat tissues. J Bone Miner Res 15: 1033-1044 Hodsman AB, Kisiel M, Adachi JD, Fraher LJ, Watson PH 2000 Histomorphometric evidence for increased bone turnover without change in cortical thickness or porosity after 2 years of cyclical hPTH (1-34) therapy in women with severe osteoporosis. Bone 27: 311-318 Holdsworth DW, Thornton M, Drost D, Watson PH, Fraher LJ, Hodsman AB 2000 Rapid small-animal DEXA using digital radiography. J Bone Miner Res 15: 2451-2457 Watson PH, Westhusin M, Watson AJ 2001 Characterization of an ovarian PTHrP pathway that promotes bovine early development in vitro*. Anatomy and Embryology 203: 175-184 Pickard BW, Hodsman AB, Fraher LJ, Watson PH 2006 Type 1 Parathyroid Hormone Receptor Nuclear Trafficking: Association of PTH1R with Karyopherin Alpha2 and Beta1. Endocrinology 147: 3326-3332
