DESCRIPTION: (provided by applicant): Previous investigations of periodontal inflammation in diabetics have held to the paradigm that increased periodontal disease in diabetics is a result of depressed inflammatory cell function, including reduced neutrophil chemotaxis and reduced phagocytosis. New preliminary data from our laboratories, however, suggest that the diabetic neutrophil is actually primed or hyperactive. We have demonstrated that neutrophils obtained from diabetics exhibit increased superoxide and protein kinase C. Other data obtained in our laboratories have established that normal patients with periodontal disease mount a strong antibody response to Porphyromonas gingivalis, the primary etiological agent associated with periodontal disease, and in particular to the cysteine proteinases collectively referred to as gingipains. Furthermore, this antibody functions in the phagocytosis and killing of p. gingivalis by normal neutrophils. What is not known, however, is how the diabetic neutrophil responds specifically to P gingivalis and to P. gingivalis components, including the gingipains. The objectives of this planning grant are to examine the neutrophil response to P. gingivalis and gingipains in Type 1 diabetic patients with periodontal disease. These studies are based on the hypothesis that increased periodontal disease in Type 1 diabetics is a sequel of increased neutrophil mediated issue injury in response to P gingivalis and to P. gingivalis components. The following specific aims are proposed: 1. To define the cellular and molecular basis of exaggerated neutrophil responses in Type 1 diabetics with periodontal disease as compared to diabetics free of periodontal disease, and normal, periodontally healthy, nondiabetic controls. a. We will evaluate neutrophil activation through measurements of superoxide production, production of cyclooxygenase-2 (COX-2), PGE2, and interleukin 1b (L-1b). These will be evaluated at both RNA and protein levels. b. We will define the specific signal transduction pathways leading to neutrophil activation ("on signals") and control of neutrophil activation ("off signals"). We will examine "on signals including know proinflammatory receptors mediated by G-protein, phospholipase C and D, diglyceride, and protein kinase C pathways. The "off" signals will include lipoxin A4 pathways mediated by polyisoprenyl phosphate signaling. 2. To define the neutrophil mediated inflammatory response to P. gingivalis and the gingipains in the Type 1 diabetic patient. a. To evaluate phagocytosis and killing of P. gingivalis by neutrophils from diabetic patients with periodontal disease and appropriate normal controls. b. To examine the antibody response of diabetic patients with periodontal disease to P. gingivalis and the gingipains. C. To determine the contribution of the gingpains to the neutrophil response by evaluation of the opsonic activity of antibody to the arginine specific gingipains (RgpA and RgpB), and to the lysine specific gingipains (Kgp), for neutrophils from diabetics and normal controls.