Description of Research Expertise

Research Interests

Functions of molecular chaperones in the immune system - modulation of antigen receptors expression and of peptide presentation.

Key words: Chaperones, BiP, GRP94, Amyloid, Light Chain, Heavy Chain, B Cell Receptor, T Cell Receptor, MHC, Peptide, Stress Response, Development.

Description of Research

The specificity of lymphocytes is due to antigen receptors - immunoglobulins, T cell receptors and MHC molecules. The proper expression of antigen receptors and their ability to recognize antigen are dependent on accessory proteins, molecular chaperones, which regulate their biosynthesis. Our work focuses on two molecular chaperones, BiP and GRP94.

BiP is a peptide binding protein that controls folding of antigen receptors by binding selectively to some peptides in the newly synthesized proteins. Because of this ability, BiP provides an important quality control function in screening somatically mutated molecules. One project in the lab concerns how BiP recognizes normal Ig sequences and distinguishes them from aggregation-prone somatic mutants. A second project examines the use of BiP as an inhibitor of the pathologic polymerization of antibodies into amyloid fibers.

GRP94 has a different mode of action and therefore biological activity. Although it binds peptides, its specificity is different from BiP. We use combinatorial genetic and biochemical techniques to characterize its preferred binder peptides and identify its peptide binding sites. Another project explores GRP94 as a T cell stimulatory molecule. We use recombinant GRP94 constructs as vehicles to deliver peptides into professional antigen presenting cells, thereby augmenting antigen presentation to T cells in cases like tumor surveillance, where T cell responses are weak. Finally, using our GRP94 knockout mice, we are characterizing its in vivo functions most important for the development of robust immune responses.

Rotation Projects for 2006-2007

1. Screening of the peptide repertoire of GRP94
2. Analysis of GRP94 deficient mice and cells
3. Chaperone-mediated tumor antigen presentation
4. Analysis of an amyloid LC-expressing transgenic mouse

Lab personnel:
Biswas, C - Research Associate
Ostrovsky, O - Postdoctoral Fellow
Makarewich, C - Technician