Molecular Aspects of Function in Dental Disease

DESCRIPTION: The long term objectives of this application are to elucidate the structure and function of the heptahelical, G protein-activating chemotactic receptors which play a key role in resistance to infection and inflammation. The Specific Aims are to: 1) identify disease-associated genetic polymorphisms in the receptors for FMLP and IL-B. 2) characterize functional effects of these polymorphisms in a mammalian expression system. 3) identify and characterize residues and domains of the FMLP receptor involved in transmembrane signaling. 4) develop molecular models of the FMLP receptor using high field 800 MHz NMR technology. 5) assess the feasibility of a purified recombinant FMLP receptor to undergo crystallization and X ray diffraction studies. Patients with localized Juvenile periodontitis (LJP) exhibit decreased response to IL-8, and FMLP, possibly due to a molecular alteration of the receptors for these chemoattractants. There are plans to use LJP as a disease model to localize important regions of these receptors, and to help understand the increased susceptibility to infections in this oligogenic disease. To achieve the long-term goals, the experimental design is to: a) use molecular genetics to elucidate structure and functions of these receptors in health and disease. This will be accomplished through collaboration with Dr. Scott Diehl, at the NIH; b) use biophysical approaches such as high field NMR to generate molecular models of this class of heptahelical receptors, through the collaboration with Dr. Slim of the Wm. M. Keck High Field Magnetic Resonance Laboratory at Yale University; and c) prepare a purified recombinant FMLP receptor for future crystallization studies, by collaborating with Dr. Gosh. at the Roswell Park Cancer Institute. Assembled to address these questions is a coherent group of experienced investigators, each providing different, extensive, and powerful expertise to carry out the proposed studies. This provides a critical and unique opportunity to synergize basic research and clinical studies.