Our lab carries out discovery research focusing primarily on the regulation B lymphocyte responses. B cells are the subset of white blood cells that produce antibodies, which play critical roles in protection from infections. However, when not appropriately regulated, B cell activation and production of antibodies can lead to destructive effects including allergy, asthma, and autoimmune diseases such as lupus. In addition, defective regulation of B cell activation processes can lead to continual cell division, causing B cell leukemia or lymphoma.
B cell responses are controlled by cell surface receptors that allow them to sense the presence of antigens, tissue damage and other activated cells. Signals from these receptors determine whether individual B lymphocytes divide to produce more copies of themselves, differentiate to become antibody-secreting factories or die by cell suicide.
Cell surface receptors deliver signals to the interior of the cell through a network of signal transduction proteins. We are characterizing a specific subset of B lymphocyte signal transduction proteins and determining how these proteins fit into the network of signals that regulate cell survival, proliferation and migration. Specifically, we are investigating a new branch of a signaling pathway known to be critical for B cell activation during immune responses called the PI 3-kinase pathway. Interestingly this same signaling pathway is known to be deregulated in leukemias, lymphomas and many other cancerous cell types. Our current studies focus on the contribution of this new pathway to the survival, chemotaxis and adhesive properties of B lymphoma and leukemia cells. In addition we are determining the contribution of this pathway to normal cellular activation in the immune system leading to protective immunity or to allergic inflammation.
We are using several approaches to define the function of molecules involved in PI 3-kinase signaling and their interactions with one another, including microscopic imaging analyses which allow direct visualization of pathway activation and resulting protein movements inside living cells (see figure below). We also use genetic gain- and loss-of-function studies and proteomic analyses to define the structure and functional significance of signal transduction complexes. The results of our research will improve our understanding of how normal B cells are regulated and how they become de-regulated in various types of diseases such as leukemia, autoimmunity and immunodeficiency.
We have full laboratory capabilities for molecular biology and cell biology studies. Our lab has particular expertise and capabilities in fluorescence-based cellular analyses. We currently manage a 3-color live-cell imaging confocal microscopy facility (UltraView LCI) and are currently establishing a new 8-color flow cytometry analysis and training facility.
Canadian Institutes for Health Research (2009 - 2014)
Regulation of B lymphocyte activation and migration during the germinal centre response
Canadian Cancer Society (2008-2011)
Regulation of phosphatidylinositol 3-kinase signaling during lymphocyte activation: role of lipid phosphatases and novel PH domain effector proteins
Canadian Foundation for Innovation (2009-2012) Manitoba integrated cell purification and analysis unit
Krahn, A.K., S. Hou, K. Ma, V. Duronio and A.J. Marshall. (2004). Two distinct waves of membrane-proximal BCR signaling differentially regulated by Src homology 2-containing inositol polyphosphae 5-phosphatase. J. Immunol., 172: 331.
Allam, A., Niiro, H., Clark, E.A. and A.J. Marshall. (2004). The adaptor protein Bam32 regulates Rac1 activation and actin remodeling through a phosphorylation-dependent mechanism, J. Biol. Chem., 279: 39775-39782.
Niiro, H., A. Allam, A. Stoddard, F. Brodsky, A.J. Marshall, and E.A. Clark. (2004). The B Lymphocyte Adaptor Molecule of 32 Kilodaltons (Bam32) Regulates B Cell Antigen Receptor Internalization. J. Immunol., 173:5601-9.
Samuel M.S. Cheung, Jennifer C. Kornelson, Sen Hou, Monther Al-Alwan and Aaron J Marshall. (2007) Modulation of immunoreceptor signaling by oxidant costimulation: synergistic and specific recruitment of phosphatidylinositol (3,4) bisphosphate-binding PH domain adaptor proteins. Cellular Signaling, 19(5):902-12
Baher Nashed, Tingting Zhang, Monther Al-Alwan, Klaus Okkenhaug, Bart Vanhaesebroeck, Kent T. Hayglass and Aaron J. Marshall. (2007). Role of the phosphoinositide 3-kinase p110? in generation of type 2 cytokine responses and allergic airway inflammation. Eur. J. Immunol., 37:416-424.
Monther M. Al-Alwan, Sen Hou, Klaus Okkenhaug, Bart Vanhaesebroeck, Joel S. Hayflick and Aaron J. Marshall. (2007). Requirement for phosphoinositide 3-kinase p110? signaling in B cell antigen receptor-mediated antigen presentation. J. Immunol. 178:2328-35.
Monther Al-Alwan, Qiujiang Du, Baher Nashed, Sen Hou, Yijun Fan, Xi
Yang and Aaron J. Marshall. (2007) Follicular dendritic cell
– secreted protein (FDC-SP) regulates germinal center and antibody responses.
J.Immunol, 178: 7859-67.
Ting-ting Zhang, Klaus Okkenhaug, Kamal Puri, Zachary Knight, Kevan Shokat, Bart Vanhaesebroeck and Aaron J. Marshall. (2008) Phosphoinositide 3-kinase signaling antagonizes IgE production. J. Allergy Clin. Immunol., 122:811.
Jennifer Costantini, Samuel M.S. Cheung, Sen Hou, Hongzhao Li, Sam Kung, John Wilkins and Aaron J. Marshall. (2009) TAPP2 links phosphoinositide 3-kinase signaling to B cell adhesion through interaction with the cytoskeletal protein utrophin: expression of a novel cell adhesion-promoting complex in B cell leukemia. Blood Journal, 114:4703-12
|Sen Hou||Technician||(204) email@example.com|
|Kennedy Makondo||Research Associatefirstname.lastname@example.org|
|Sandrine LaFarge||Post Doctoral Fellowemail@example.com|
|Hongzhao Li||Ph.D. Programfirstname.lastname@example.org|
|Tingting Zhang||Ph.D. Programemail@example.com|
|Ivan Landego||B.Sc. Program||Landego@hotmail.com|
|Samantha Pauls||M.Sc. Programfirstname.lastname@example.org|