IFI16 is a Periodontitis Modulating Protein

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ABSTRACT This application is for a Mentored Career Development Award to Promote Diversity in the Dental, Oral and Craniofacial Research Workforce (K01) for Dr. Julie Marchesan. She is conducting research into the role of IFI16 as a modulator of periodontal tissue destruction via AIM2 inflammasome and cytokine/chemokine expression. The rationale for the proposed experiments is supported by the literature and preliminary data of the applicant. This award will allow Dr. Marchesan a) to become an expert in periodontal inflammation and host response, b) to train in application and interpretation of mechanistic approaches in order to increase the quality of the translational research she currently conducts, c) to develop an independent research career that will allow her to collaborate with clinical and basic researchers, and d) to increase the representation of Latino women that are in academia and independently funded in oral health research. A multidisciplinary team of experts has agreed to support Julie during this research proposal based upon funding of this application. The team and main expertise that justified inclusion of the researcher in this application are: a) Dr. Steve Offenbacher (co-mentor, translational research in periodontology), b) Dr. Jenny Ting (co-mentor, host response), c) Dr. Jennifer Webster-Cyriaque (support team, microorganisms-host interactions), Dr. John Preisser (support team, biostatistics) and Dr. Andrea Azcarate-Peril (support team, characterization of microbial populations). The combination of this mechanistic proposal with the guidance afforded by these successful researchers will provide the necessary environment for Dr. Marchesan to become a successful, independent investigator and highly represent diversity in academia. Periodontal disease affects almost half of the American adult population and is a major cause of tooth loss. The paucity of pharmacologic agents available to treat periodontitis provides sufficient justification for studying the host response and potential inflammatory modulators of periodontitis. Dr. Marchesan's preliminary data demonstrate that IFI16 is expressed in multiple cells of human periodontal tissues, including epithelial, endothelial, fibroblasts and cells of the inflammatory infiltrate. She also showed that IFI16 overexpression decreases the chemokine response. The finding that the lack of this protein in knockout animals significantly increases the amount of periodontal bone loss strengthens the evidence that this protein modulates inflammation. The proposed application will utilize mechanistic approaches (overexpression, silencing, knockout animals, bone marrow-transplants, protein inhibition) to study the role of IFI16 as a modulator of the periodontal host response. This project will evaluate IFI16 as a modulator of the periodontal host response in vitro (SA1); we propose to explore a) IFI16 hindering inflammatory tissue destruction in vivo and b) the utilization of a currently available therapeutic agent (SA2); and we will identify the main cellular source of IFI16 that is responsible for inflammatory response modulation (SA3). While there are no current therapies specifically targeting IFI16, there are available drugs that target products of AIM2-inflammasome, such as caspase-1 inhibitors. The long-term goal of these experiments is to better understand modulation of inflammation to control periodontal tissue destruction. Dr. Marchesan's research will provide a basis for understanding inflammasome modulation in periodontal tissue destruction and allow the development of a novel future project exploring inflammasomes and potential therapies for treating periodontitis by the end of this 5-year funding period.