The physiological role of neutrophils (PMN) is to protect the host from invading microbes by emigration from blood vessels, chemotaxis, phagocytosis, and destruction of the invading organism. The neutrophil receptor for formylated peptides such as N-formyl-1-methionyl-1-leucyl-1- phenylalanine (FMLP) is involved in PMN activation, secretion, as well as chemotactic response to certain stimuli. The FMLP receptor is of great biological significance since it plays a crucial role in neutrophil response and motility. However, little is known about the functional domains of the receptor, as well as its genetic features. In this study we propose to characterize the functional domains of the receptor which are involved in ligand binding and in the activation of G proteins by: a) constructing synthetic peptides corresponding to different portions of the receptor components, and b) recombinant expression and site-directed mutagenesis. We also propose to characterize genetic features of the human FMLP receptor by: a) chromosome localization of the gene coding for the receptor, and b) investigating FMLP receptor DNA homology/differences between individuals. In localized juvenile periodontitis (LJP), patients' PMN exhibit decreased chemotaxis and decreased FMLP binding. An alteration in the chemotactic peptide receptor is suspected to be a predisposing factor for this disease. It is not clear as to whether this alteration is qualitative, quantitative or at a post-receptor level; also unclear is the genetic aspect of this disease. Thus, we also propose to analyze some of the biochemical, functional and genetic features, of the FMLP receptor in LJP patients, and compare these features to those from normal subjects by: a) RFLP analysis of a large number of LJP patients and normal controls; and b) functional mapping of the FMLP receptor, in PMN from both normal individuals as well as in LJP patients, using monoclonal antibodies. The results from these studies will provide valuable information on the mechanisms of FMLP receptor function and processing, as well as normal neutrophil activation. In addition, they will also provide a better understanding of the molecular basis of the PMN defect reported in LJP.
| Boehm, Tobias Konrad; Sojar, Hakimuddin; Denardin, Ernesto (2010) Concentration-dependent effect of fibrinogen on IgG-specific antigen binding and phagocytosis. Cell Immunol 263:41-8 |
