Lab Research Focus
The main goal of my research is to understand the role of genetic factors in the normal function of the immune system and in development of immunological diseases such as systemic lupus erythematosus and systemic vasculitis. Our approach has focused on receptors for immunoglobulin as a model system and has explored molecular mechanisms of receptor signaling and the molecular basis for receptor polymorphisms in humans. Human receptors for immunoglobulin are comprised of multiple genes and gene clusters leading to a marked diversity in biological properties ranging from ligand binding to signal transduction. These receptors, expressed on many cell types including B cells, natural killer cells, and phagocytes, link important components of the innate and acquired immune systems. Other genes and gene families are being pursued as they are identified as candidate genes through genome scans, family studies and linkage studies. These genes include complement receptors, cytokine genes and their promoters and signal transduction molecules (gamma and zeta chains).
A combination of techniques is used to evaluate receptor function. Protein-based characterization complements yeast two-hybrid identification of intracellular signaling molecules. Stable transfection of point mutants and deletion mutants allows biologic characterization of critical residues within functional domains. Fluorescent probes of live cell function are monitored by digital microscopy and by quantitative flow cytometry, and various assays of intact cell function (phagocytosis, degranulation, respiratory burst, cytokine production) are used to measure integrated cell programs. Specific polymorphisms are identified by direct automated fluorescent sequencing and typically, allele specific PCR is used to genotype individuals for each polymorphism. By combining direct experimental investigations of receptors, their biologies and their polymorphisms with national and international collaborative networks, identification of important risk factors underlying immunologic diseases and autoimmunity are sought.
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