My career goals are to pursue the role of autophagy in bone tissue. Recent studies have demonstrated the potential roles that autophagy may play in the bone system, and in particular, in bone disease. Autophagy's role has only recently been investigated in diseases such as osteoporosis and osteoarthritis. The study of autophagy in the immune system will allow me to understand how autophagy may contribute to diseases in bone cells. Ultimately, training in this area will allow me to contribute an unprecedented level of expertise in the nascent field of autophagy research focused in the bone system, ideally as an independent investigator.
Thesis: Addressing structural and functional alterations in V-ATPase due to disease causing mutations
The focus of my graduate thesis was to elucidate the effects of disease causing mutations in V-ATPase, a proton pumping enzyme responsible for bone resorption. Knowledge of the effects of these mutations lead to new discoveries into the topological features and structural characteristics of V-ATPase, a membrane protein for which limited structural characteristics are known.
Work from this thesis resulted in a first authorship and co-authorship publication, listed in Publications.
Expertise gained in:
Thesis: Role of PI3K signalling pathway in immune cell response to developmental and bacterial effectors
The focus of my undergraduate thesis project was to discover the role the PI3K downstream effectors played in macrophage immune response to effectors. These downstream effectors AKT, and BTK, were found to be critical in conveying the cellular response to variety of stimuli, such as bacterial invasion, and developmental ligand response.
Work during this thesis resulted in technical skills development useful for future studies, and are listed in Technical Skills.
Expertise gained in:
1. Bhargava, A., Kartner, N., Voronov, I., Wang, Y., Glogauer, M., and Manolson, M. R444L missense mutation responsible for infantile osteopetrosis alters V-ATPase a3 structure and ER processing. (Manuscript in preparation, 2011)
2. Kartner, N., Yao, Y., Bhargava, A., Manolson, M., Topology, glycosylation and conformational changes in the membrane domain of the V-ATPase a subunit. (Manuscript submitted to JBC [ID:JBC/2011/334490], 2011)
3. Durand M., Komorova S.,Bhargava A., Li K., Fiorino C., Nabavi N., Manolson M.F., Harrison R.E., Dixon S.J., Sims S.M., Mizianty M.J., Kurgan L., Boire G., Lucena-Fernandes M.F., deBrum-Fernandes A.J., Monocytes from patients with osteoarthritis display increased osteoclastogenesis and subsequent bone resorption: the in vitro osteoclast differentiation in arthritis (IODA) study
(Manuscript submitted to Arthritis and Rheumatism [ID: ar-11-1887], 2011)
1. Bhargava, A., Kartner, N., Voronov, I., Wang, Y., Glogauer, M., and Manolson, M. R444L missense mutation responsible for infantile osteopetrosis alters V-ATPase a3 structure and ER processing.
Canadian Arthritis Network Conference, Quebec City, 2011
2. M.J. Mizianty, A. Bhargava, A.J. de Brum-Fernandes, S.J. Dixon, M. Durand, R.E. Harrison, S.V. Komarova, L. Kurgan, M.F. Lucena-Fernandes, M.F. Manolson, S.M. Sims, Multivariate diagnostic model for osteoarthritis highlights the importance of osteoclastogenesis and expression of interleukin 1 receptors.
Canadian Arthritis Network Conference, Quebec City, 2011
3. Bhargava, A., Glogauer, M., and Manolson, M. Elucidating the Mechanism by which the Human R444L and G405R Point Mutations in the V-ATPase 'a3' Subunit Leads to Osteopetrosis
American Society for Bone and Mineral Research,Toronto, 2010