ABSTRACT This K08 application is to support the research and career development of Dr. Adam Lietzan, a periodontist and research assistant professor at the UNC Adams School of Dentistry. This award will provide Dr. Lietzan an intensive mentored experience in order for him to complete the transition to an independent clinician-scientist with a research program focused on understanding the dynamic immune responses to microbial dysbiosis during periodontitis. As such, a training plan including didactic, hands-on, and career development experiences has been put forth to enable this transition. During this award, Dr. Lietzan will gain skills/knowledge in: 1) host- pathogen interactions, 2) cutting-edge techniques to evaluate immunological responses, 3) proposal development, scientific writing, and oral presentations, and 4) leadership. This will allow Dr. Lietzan to develop collaborative opportunities with scientists and clinicians across multiple disciplines and a high-quality independent research program. Dr. Lietzan has established a multi-disciplinary team to provide expertise in research training and mentorship in career development. Together this team will provide foundational training in immunology, cell-based techniques, and animal models as well as help advise with critical aspects of the career development. This will be coupled with a strong research plan. The onset of inflammation is facilitated by a cascade of signaling molecules released by both canonical (e.g. macrophages) and noncanonical immune cells (e.g. epithelial cells). The highly potent interleukin (IL)-1 family of signaling molecules primarily induces inflammatory damage and is heavily implicated in periodontitis development and severity. Interleukin-37, an IL- 1 family member, conversely suppresses inflammation and has been shown to be dysregulated in severe forms of periodontitis. The oral epithelial cell (OEC), which acts as a physical, chemical, and immunological shield against infection, highly expresses IL-37 when exposed to microbial stimuli. Despite this knowledge, the impact of IL-37 on OECs and the molecular interactions that underlie its anti-inflammatory bioactivity in periodontitis remains largely uncharacterized. Here Dr. Lietzan seeks to fill this knowledge gap by dissecting the cellular pathways that IL-37 modulates during microbial challenge of OECs using in vitro and in vivo model systems. The molecular interactions between IL-37 and its receptors, which are highly expressed on OEC, will also be delineated. Lastly, the relevance of glycosaminoglycans (GAGs) within the periodontal extracellular matrix on IL- 37 bioactivity will be investigated. Successful completion of this proposal will inform the development of new and/or improve existing IL-37-centric interventions aimed at modulating chronic inflammation, such as that associated with periodontitis. Together these training and research activities will be a significant step towards Dr. Lietzan achieving his lo...