Fibrin-neutrophil interaction in periodontitis immunopathology

Mucosal immune responses are key for the regulation of oral tissue homeostasis, but when disrupted will lead to disease. Despite well-established appreciation of this general concept, specific mechanisms of oral mucosal immunity are not yet completely understood. Mendelian diseases have been instrumental in understanding oral health and disease by uncovering genes and pathways implicated in human immunity and mucosal homeostasis. One Mendelian disease clearly linked to oral mucosal disease is Plasminogen (Plg) deficiency. Plg, is the precursor of the active protease plasmin, which is the primary fibrinolytic enzyme in both intravascular and extravascular space. Homozygous or compound heterozygous mutations in the human Plg gene (PLG) typically lead to severe oral mucosal disease, suggesting a critical role for this protease in mucosal immunity. Indeed, these patients present with fibrin deposition at mucosal sites and oral mucosal disease (ligneous periodontitis). In ligneous periodontitis, excessive deposition of fibrin is hypothesized to lead to severe soft tissue and alveolar bone destruction, and often results in the loss of the entire dentition in adolescence. However, the mechanistic link between mucosal fibrin deposition and immunopathology is not yet understood. Mucosal inflammation and fibrin deposition in areas surrounding the dentition and destruction of underlying bone are also the hallmarks of the common form of periodontitis. Based on extensive preliminary data, Dr. Silva has formulated a central hypothesis that mucosal fibrin deposition promotes periodontitis progression through the local engagement and activation of infiltrating neutrophils. To test this hypothesis, Dr. Silva will pursue three specific aims: (1) Determine the role of neutrophil-fibrin engagement in periodontal bone loss under compromised and normal fibrinolytic conditions; (2) Determine the contribution of fibrin-neutrophil engagement for the induction of neutrophil effector functions in vitro; and (3) Pharmacologically target fibrin-neutrophil effector functions to prevent periodontitis bone loss. The mentored phase of this research will be conducted in the laboratories of Dr. Silva’s primary mentors, Drs. Moutsopoulos and Bugge at NIDCR, which have all required equipment and facilities in addition to an excellent intellectual environment for periodontal and fibrinolysis research. For scientific research training and to help with her career growth, Dr. Silva has assembled a strong advisory committee to enhance her knowledge in fibrin biology, immunology and neutrophil biology. She has also assembled an expert consultant team to help her develop new research skills including live cell imaging and computer-based image analysis. In addition, Dr. Silva will attend seminars, workshops and courses provided at NIH to improve her scientific communication, grant writing, mentoring and leadership skills. This research, along with specific training activities, will generate publications and preliminary data to help Dr. Silva to achieve her career goal of becoming an independent researcher in the field of oral health and disease.