个人简介

M.D. (Doctor of Medicine)

研究领域

Molecular Biology and Disease

Murine models of skeletal development - We are using genetic approaches in transgenic mice to explore the influence of specific genes (for example, the tumor suppressor, PTEN) on skeletal development and bone homeostasis. The primary methods of assessment include microcomputed tomography and immunohistochemistry. Our primary collaborators in this area are Drs. B. Hallgrimsson, S.K. Boyd, and P. Salo (University of Calgary). Immunoglobulin-induced inflammatory arthritis - We are exploring the potential role of various genes to regulate the severity and duration of joint inflammation and damage using the KBxN murine model of inflammatory arthritis. In collaboration with Dr. H. Vogel (University of Calgary) we have also carried out a 1H-NMR-based metabolomics study of this model of arthritis. Breast cancer bone metastasis - High-resolution microcomputed tomography and bioluminescence are being used to quantify in vivo bone damage caused by a luciferase-expressing osteolytic human breast cancer cell line (MDA-MB-231): bone metastases are induced to yield a murine xenograft model for drug evaluation. The primary aim of this initiative is to evaluate various experimental therapies aimed at preventing and diminishing these lesions and attenuating the osteoclast-mediated bone destruction they produce. Our co-investigators in this study are Drs. B. Hallgrimsson and S.K. Boyd, University of Calgary). Prostate cancer model development – The laboratory developed a mouse strain with a system that allows temporal control over gene alterations in the murine prostate. This technology allows for a more ‘age appropriate’ evaluation of gene function, and thus represents and improvement over current models in which gene excisions occur during development of the gland. We are studying the role of several members of the phosphatidylinositol signaling pathway in the genesis of prostate cancer. Role of Pten and Smad4 in regulating T cell function in the experimental autoimmune encephalomyelitis model (EAE) - Using a conditional mutagenesis approach we are studying the effects of specific gene deletions in CD8+ T cells involved in the pathogenesis of a disease model (myelin oligodendrocyte glycoprotein-induced EAE) that has some similarities to multiple sclerosis (MS) in humans. Mutagenesis and carcinogenesis in murine models of lung cancer - We are studying mutagenesis (using the BigBlue in vivo mutational reporter system) and lung cancer carcinogenesis in A/J mice lacking specific DNA repair systems (including deficiencies of methyguanine methytransferase, MGMT, and the DNA mismatch repair molecule, MSH2). We are also setting up a novel model of lung adenocarcinoma, and mesothelioma, as this will allow translational studies. Lastly, a collaborative study with Dr. M. Weinfeld (Cross Cancer Institute) is aiming to elucidate the in vivo function of the polynucleotide kinase gene. Prion research - The purpose of the initiative is to try to identify the normal function(s) of the protein product of prion gene (Prnp). For example, we have found that the expression of the prion protein regulates the course of a specific T cell-dependent autoimmune response. We are investigating several genes for their ability to regulate susceptibility to and severity of prion disease (transmissible spongiform encephalopathies – TSEs) using mouse-adapted scrapie prions as the pathogenic agent. We are setting up a system for targeted transgenesis via homologous recombination in murine embryonic stem cells for the purpose of studying and comparing the expression prion gene mutants in vivo. We are also collaborating with Dr. G. Zamponi (University of Calgary) on a study involving electrophysiological aspects of prion gene function.

近期论文

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Downey CM, Horton CR, Carlson BA, Parsons TE, Hatfield DL, Hallgrímsson B, Jirik FR. Osteo-Chondroprogenitor-Specific Deletion of the Selenocysteine tRNA Gene, Trsp, Leads to Chondronecrosis and Abnormal Skeletal Development: a Putative Model for Kashin-Beck Disease. PLoS Genetics. 2009 (in press). Bondareva A, Downey C, Ayres F, Liu W, Boyd SK, Hallgrimsson B, Jirik FR. The lysyl oxidase inhibitor, beta-aminopropionitrile, diminishes metastatic colonization potential of circulating breast cancer cells. PLoS ONE. 2009;4(5):e5620. Epub 2009 May 19. Pushie MJ, Rauk A, Jirik FR, Vogel HJ. Can copper binding to the prion protein generate a misfolded form of the protein? Biometals. 2009, 22(1):159-175. Weljie AM, Newton J, Jirik FR, Vogel HJ. Evaluating low-intensity signals in quantitative proton NMR mixture analysis. Analytical Chem. 2008 (accepted; Epub Oct 2008) Luchman HA, Benediktsson H, Peterson A, Jirik FR. The pace of prostatic intraepithelial neoplasia development is determined by the timing of Pten tumor suppressor gene excision. PLoS ONE. 2008, 3(12):e3940. Tsutsui S, Johnson T, Hahn J, Ali Z, Jirik FR. Absence of the cellular prion protein exacerbates and prolongs neuroinflammation in experimental autoimmune encephalomyelitis (EAE). Am J Pathol. 2008, 173(4):1029-1041 Heit B, Guan Z, Robbins S, Colarusso P, Downey C, Miller BJ, Jirik FR, Kubes P. PTEN functions to ‘prioritize' chemotactic clues and prevent ‘distraction' in migrating neutrophils. Nature Immunol. 2008, 9(7):743-752. Khosravani H, Zhang Y, Tsutsui S, Hameed S, Hamid J, Chen L, Villemaire M, Ali Z, Altier C, Jirik FR, Zamponi GW. Prion protein decreases excitotoxicity via attenuation of NMDA receptor function. J Cell Biol. 2008, 181:551-565. Johnson T, Tsutsui S, Jirik FR. Antigen-induced Pten gene deletion in T cells exacerbates neuropathology in experimental autoimmune encephalomyelitis (EAE). Am J Pathol. 2008, 172:980-992. Luchman HA, Friedman HC, Villemaire M, Peterson AC, Jirik FR. Temporally controlled prostate epithelium-specific gene alterations. Genesis. 2008, 46(4):229-234. Sandercock LE, Hahn JN, Giesbrecht JL, Luchman HA, Peterson LA, Jirik FR. Mgmt-deficiency sensitizes the lung to the mutagenic effects of the tobacco carcinogen 4-methylnitrosamino-1(3-pyridyl)-1-butanone (NNK). Carcinogenesis. 2008, 29(4):866-874. Cummings KJ, Kalf D, Moore S, Miller BJ, Jirik FR,Wilson RJA. Superoxide dismutase-1 influences the timing and post-hypoxic stability of neonatal breathing. Adv Exp Med Biol. 2008, 605:133-138.J Johnson T, Tsutsui S, Jirik FR. Antigen-induced Pten gene deletion in T cells exacerbates neuropathology in experimental autoimmune encephalomyelitis (EAE). Am. J. Pathol. 2008, 172:980-992. Luchman HA, Friedman HC, Villemaire M, Peterson AC, Jirik FR. Temporally controlled prostate epithelium-specific gene alterations. Genesis 2008 (in press) Sandercock LE, Hahn JN, Giesbrecht JL, Luchman HA, Peterson LA, Jirik FR. Mgmt-deficiency sensitizes the lung to the mutagenic effects of the tobacco carcinogen 4-methylnitrosamino-1(3-pyridyl)-1-butanone (NNK). Carcinogenesis 2008 (in press). Weljie AM, Dowlatabadi R, Miller BJ, Vogel HJ, Jirik FR. An Inflammatory Arthritis-Associated Metabolite Biomarker Pattern Revealed by (1)H NMR Spectroscopy. J. Proteome Res. 2007, 6(9):3456-3464. Ford-Hutchinson AF, Ali Z, Lines SE, Hallgrimsson B, Boyd SK, Jirik FR. Inactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnormalities and skeletal overgrowth. J. Bone Miner. Res. 2007, 22(8):1245-59. Starnes, LM, Downey CM, Boyd SK, Jirik FR. Increased bone mass in male and female mice following tamoxifen administration. Genesis. 2007, 45(4):229-35. Hallgrimsson B, Lieberman DE, Liu W, Ford-Hutchinson AF, Jirik FR. Epigenetic interactions and the structure of phenotypic variation in the cranium. Evolution Develop. 2007, 9(1):76-91.