Molecular Genetics, Structure, and Transgenic Studies of Chemoattractant Receptors

My laboratory's research interests are directed at understanding the molecular events involved in mediating the inflammatory and immune response in both normal and pathological conditions. Much of our work is focused on studies of the complement anaphylatoxin receptors. These receptors have been implicated in playing major roles in numerous diseases, including rheumatoid arthritis, asthma, psoriasis, lupus, and atherosclerosis.

To examine the requisite role of the anaphylatoxin receptors in these and other diseases, we have generated several "knock-out" mice in which the genes encoding these receptors and their ligands have been selectively inactivat-ed by homologous recombination methods. These mice have already been employed in studies of a mouse model of asthma which has revealed that the C3a anaphylatoxin peptide may be a major contributor in the recruitment of eosinophils into the lung airways during the early stages of asthma.

The overall goal of our research program for the next five years is to increase our understanding of the specific and overall roles that complement anaphylatoxin peptides and their receptors play in inflammation and immunity. These studies will be carried out using the complement "knock-out" mice generated in our laboratory. We will determine the cells in peripheral blood and tissues that express the receptors in vivo, and determine biological functions mediated by these cells after ligand stimulation. In addition, we will determine the overall effect of these receptors in pul-monary and skin diseases as well as in bacterial sepsis. "Knock-out" animals will also be generated in which genes that are thought to control inactivation of the complement anaphylatoxin peptides will be disrupted. This will allow us to examine in vivo the molecular regulation of these potent mediators of inflammation.