Mitchell, Christina - Monash University - Department of Biochemistry and Molecular Biology

研究领域

The research group led by Professor Mitchell is currently researching the role of lipid phosphatases in development and human disease, and is also characterising the FHL family of LIM proteins in muscle disorders. The team has two major fields of research: A. Characterisation of phosphoinositide phosphatases in development and disease. PI3-kinase signalling has a critical role in many essential cell processes including cell survival, migration/invasion and protein trafficking. Many components of the PI3-kinase pathway exhibit altered expression or mutations in human disease and cancer leading to oncogenic signalling. Phosphoinositide phosphatases that regulate PI3-kinase pathway are also associated with human disease, including breast cancer, ciliopathy syndromes, diabetes/insulin signalling, neuronal disorders, leukaemia and developmental disorders. Our laboratory focusses on identifying the role of phosphoinositide 3-, 4- and 5-phosphatases in human disease, such as breast cancer, childhood brain cancer, glioblastoma, ciliopathies and renal disease. In addition, our research examines the role of phosphoinositide phosphatases in innate immunity and embryonic development. We have generated several ubiquitous and tissue-specific knockout, disease and cancer mouse models complemented with genetically manipulated mammalian cell lines, to facilitate our studies investigating the role of phosphoinositide phosphatases in human disease and development. B. Mechanism of Skeletal muscle disease and identification of novel therapies Professor Mitchell's group has also worked towards characterising the FHL family of LIM proteins for over a decade and has cloned several isoforms including FHL1A and FHL1B (SLIMMER), which are highly expressed in skeletal and cardiac muscle. The project aims to identify the role of these proteins in muscle, which have been shown to regulate critical functions including myoblast fusion, sarcomere formation, postnatal muscle growth and strength. More recently the Mitchell laboratory has examined fhl1 gene mutations as the cause of several human muscle diseases including Reducing body myopathy. This discovery has broadened the laboratory's research focus to investigate mechanisms underlying human muscle disease, for the identification of novel therapies. This strategy also includes the first group which is examining the role of phosphoinositide signalling pathway in regulating muscle homeostasis.

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Davies EM, Kong AM, Tan A, Gurung R, Sriratana A, Bukczynska PE, Ooms LM, McLean CA, Tiganis T and Mitchell CA. (2014) Differential SKIP expression in PTEN-deficient glioblastoma regulates cellular proliferation and migration. Oncogene (accepted) Wilding BR, McGrath MJ, Bonne G and Mitchell CA. (2014) FHL1 mutations that cause clinically distinct human myopathies form protein aggregates and impair myoblast differentiation. Journal of Cell Science 127(10):2269-81 McGrath MJ, Binge LC, Sriratana A, Wang H, Robinson PA, Pook D, Fedele CG, Brown S, Dyson JM, Cottle DL, Cowling BS, Niranjan B, Risbridger GP, Mitchell CA. (2013) Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer. Cancer Research 73(16):5066-5079 D'Arcy CE, Feeney SJ, McLean CA, Gehrig SM, Lynch GS, Smith JE, Cowling BS, Mitchell CA, McGrath MJ. (2013) Identification of FHL1 as a therapeutic target for Duchenne muscular of FHL1 as a therapeutic target for Hum Mol Genet 23(3):618-636 Bertucci MC and Mitchell CA (2013) Phosphoinositide 3-kinase and INPP4B in human breast cancer. Annals of the New York Academy of Sciences 1280(1):1-5 Conduit SE, Dyson JM and Mitchell CA (2012) Inositol polyphosphate 5-phosphatases; new players in the regulation of cilia and ciliopathies. Invited review for FEBS Letters 586(18):2846-57 Hakim S, Bertucci MC, Conduit SE, Voung DL and Mitchell CA (2012) Inositol polyphosphate phosphatases in human disease. In "Phosphoinositides and Disease" by Springer, Curr Top Microbiol Immunol 362:247-314 Dyson J, Fedele C, Davies M, Becanovic J, and Mitchell CA. (2012) Phosphoinositide phosphatases: just as important as the kinases. In "Phosphoinositides I: Enzymes of Synthesis and Degradation" by Springer, Subcell Biochem 58:215-279. Davies EM, Sheffield DA, Tibarewal P, Fedele CG, Mitchell CA and Leslie NR. (2012) The PTEN and myotubularin phosphoinositide 3-phosphatases: linking lipid signalling to human disease. In "Phosphoinositides I: Enzymes of Synthesis and Degradation" by Springer, Subcell Biochem 58:281-336. Astle MV, Ooms LM, Cole AR, Binge LC, Dyson JM, Layton MJ, Petratos S, Sutherland C, Mitchell CA. (2011) Identification of a proline-rich inositol polyphosphate 5-phosphatase (PIPP): collapsin response mediator protein 2 (CRMP2) complex that regulates neurite elongation. J. Biol. Chem. 286(26):23407-18