Research Project
10480159
PROJECT SUMMARY/ABSTRACT The mouth is signified as ?the window to general health?. However, oral health and general health have long been perceived as separate entities. Pathological conditions that arise in the mouth can have a profound impact on systemic health. Periodontitis is a common oral inflammatory disease that affects nearly 10% of the global population and 50% of Americans aged >30 years. Periodontitis and associated bacteria have been reported to affect the course and pathogenesis of several systemic diseases, like diabetes, endocarditis, inflammatory bowel disease (IBD), rheumatoid arthritis, preterm birth, and osteoporosis. Increased prevalence of periodontitis and periodontal pathogens is noted in IBD patients. IBD is characterized by chronic inflammation of the gastrointestinal tract, and primarily includes Crohn's disease and ulcerative colitis. Over 3 million people in the US are affected by IBD. Both periodontitis and IBD impose enormous social, psychological, and economic burden on people and health services. To date, the etiology of IBD remains largely unknown, and the potential causal role of periodontitis in IBD remains poorly investigated. Genome-wide association studies have identified sequence variants in the Interferon Regulatory Factor 8 (Irf8) gene as significant risk factors for IBD. Our previous work shows that Irf8 is critical for periodontal homeostasis and osteoclast regulation. However, to date, no studies have investigated the direct role of Irf8 in periodontitis and IBD, which represents a significant knowledge gap that is addressed in this proposal. The long-term goal of the proposed research is it to elucidate the molecular mechanisms governing periodontitis process and the potential causal role of periodontitis and associated bacteria in IBD. This project leverages complementary in vitro and in vivo mechanistic approaches and next generation sequencing to pursue the following aims a) determine how Irf8 deficiency shapes oral microbiota and transcriptional and epigenetic landscapes that modulate periodontal disease process; and b) determine how Irf8 deficiency along with dysbiotic gut microbiota creates an opportunistic environment for oral bacteria to colonize the gut and elicit intestinal inflammation. This will enable us to identify how Irf8 shapes a) genes and signaling mechanisms that modulate immunoinflammatory responses in periodontitis and IBD; and b) the potential cellular and humoral responses by which oral bacteria elicit intestinal inflammation. Our project delineates the complex interrelationship between periodontitis and IBD. This project has the potential to significantly advance the fields of periodontitis and IBD research. It will uncover the immunoinflammatory responses regulated by Irf8 and pathways upstream and downstream of Irf8 that could be potentially targeted to develop interventional and therapeutic approaches for periodontitis and IBD. This project lays the platform for future clinical and translational research to improve oral health, which will result in novel and innovative ways to treat systemic diseases initiated by periodontitis and oral bacteria.
