Ralph Snyderman, MD
Adjunct Professor of Medicine
Chancellor Emeritus of Duke University
2424 Erwin Road, Suite 1101
Durham, NC 27705
- MD, State University of New York at Brooklyn, 0
Phagocytic leukocytes including neutrophils and macrophages play a critical role in immunologically mediated host defense and tissue destruction. These cells migrate to and become activated at sites of inflammation in response to chemoattractant factors, including -C5a, interleukin 8 (IL-8), formylated peptides (e.g. fMLP) Leukotriene B4(LTB4) and platelet activating factor (PAF). The responses of leukocytes to chemoattractants is mediated by G protein coupled receptors. The focus of this laboratory has been to define the mechanisms which regulate chemoattractant receptors activation, desensitization and priming. To study the mechanisms of leukocyte activation, we have developed genetic and biochemical techniques. We constructed epitope-tagged human formylpeptide, C5a, PAF, LTB4 and IL-8 receptor cDNAs and expressed receptors either singly or multiply in a cell line which mimics responses of human inflammatory cells. These RBL-2H3 cells are a basophilic cell line which endogenously contains thrombin receptors. Using this model system, we are studying desensitization, cross-desensitization and priming, a phenomenon whereby one stimulus leads to greatly enhanced responsiveness to a second stimulus. Our data have demonstrated an unexpected and interesting complexity in chemoattractant receptor phosphorylation and desensitization. We have defined kinases involved in receptor desensitization. Furthermore, we have identified motifs in the cytoplasmic tails of IL-8 and PAF receptors that appear to be critical for cell activation by their respective ligands. We have also identified a new form of chemoattractant receptor desensitization, termed class desensitization. A major effort of this laboratory is directed at defining the precise molecular events controlling leukocyte activation.
Clinical trials: None
Areas of expertise and national recognition: Immunology, Inflammation, Rheumatology and Medical Center Adminstration.