Protein/antibody engineering and FcRn biology: A primary focus of our work is to investigate how the non-classical Fc receptor, FcRn, functions as a transporter and regulator of immunoglobulin G (IgG) levels throughout the body. This has significance to understanding how an effective humoral response develops, which in turn relates to multiple aspects of human health (immunodeficiency, pathogen resistance etc.). We are using a variety of live cell fluorescence imaging methodologies to investigate how FcRn and its IgG ligand traffick within and across cells. We are also using protein engineering to develop engineered antibodies that are altered in their binding properties for FcRn and, as such, can modulate FcRn function. These studies have direct relevance to the generation of improved antibodies for use in therapy.
Autoimmunity (multiple sclerosis): A second area of interest in our laboratory is to gain insight into the factors which, at the T cell level, lead to autoimmunity. We are studying murine experimental autoimmune encephalomyelitis, a representative model of multiple sclerosis. Our research involves an analysis at the molecular and cellular levels of antigen recognition by T cell receptors expressed by autoreactive T cell clones. Our overall goal is to understand how such T cells become triggered to become pathogenic, which in turn has direct relevance to delineating the processes that lead to overt autoimmunity.
Fluorescence microscopy and technology development: A central aspect of our current work is to develop methods for image analysis for cellular microscopy, with a particular interest in single molecule imaging. For example, we have recently used theoretic and analytical approaches to obtain, and experimentally verify, a novel resolution measure that overcomes the limits of classical criteria such as Rayleigh′s resolution criterion. Combined with these studies, we are also developing new imaging configurations at the hardware level, such as a microscopy set up that allows for the simultaneous imaging of multiple planes in a cell. In addition to being of general importance, these methods are being used to address questions of biological relevance in the laboratory.
RECENT PUBLICATIONS
Ober, R.J., Martinez, C., Lai, X., Zhou, J. and Ward, E.S., "Exocytosis of IgG as mediated by the receptor, FcRn: an analysis at the single-molecule level," Proc. Natl. Acad. Sci. USA, 101:11076-11081, 2004
Ward, E.S., Martinez, C., Vaccaro, C., Zhou, J., Tang, Q. and Ober, R.J., "From sorting endosomes to exocytosis: association of Rab4 and Rab11 GTPases with the Fc receptor, FcRn, during recycling," Mol. Biol. Cell., 16:2028-2038, 2005
Ram, S., Ward, E.S. and Ober, R.J., "Beyond Rayleigh′s criterion: a resolution measure with application to single molecule microscopy," Proc. Natl. Acad. Sci. USA, 103:4457-4462, 2006
Vaccaro, C., Bawdon, R., Wanjie, S., Ober, R.J., and Ward, E.S., "Divergent activities of an engineered antibody in murine and human systems have implications for therapeutic antibodies" Proc. Natl. Acad. Sci. USA, 103:18709-18714, 2006
P. Prabhat, Z. Gan, J. Chao, S. Ram, C. Vaccaro, S. Gibbons, R.J. Ober, E.S. Ward, "Elucidation of intracellular recycling pathways leading to exocytosis of the Fc receptor, FcRn, by using multifocal plane microscopy" Proceedings of the National Academy of Sciences, in press, 2007
SIGNIFICANT PUBLICATIONS
Ward, E.S., Gussow, D., Griffiths, A., Jones, P.T. and Winter, G., "Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli," Nature, 341:544-546, 1989
Fields, B.A., Ober, B., Malchiodi, E.L., Lebedeva, M.I., Braden, B., Ysern, X., Kim, J-K., Shao, X., Ward, E.S. and Mariuzza, R.A., "Crystal structure of the Vα domain of a T cell antigen receptor," Science, 270:1821-1824, 1995
Ghetie, V., Popov, S., Borvak, J., Radu, C., Matesoi, D., Medesan, C., Ober, R.J. and Ward, E.S., "Increasing the serum persistence of an IgG fragment by random mutagenesis," Nature Biotechnol., 15:637-640, 1997
Thatte, J., Qadri, A., Radu, C. and Ward, E.S., "Molecular requirements for T cell recognition by an MHC Class II restricted T cell receptor: the involvement of the fourth hypervariable loop of the Vα domain," J. Exp. Med., 189:509-519, 1999
Vaccaro, C., Zhou, J., Ober, R.J. and Ward, E.S., "Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels," Nature Biotechnol., 23:1283-1288, 2005
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