Therapeutic Targeting of Apical Periodontal T-Cells in Chronic Oral Inflammation

University Of California Los Angeles, Los Angeles CA

Investigators

Abstract

ABSTRACT Apical periodontitis is a chronic inflammatory disease that results from advanced dental infection of the root canal system. Studies of global populations provide an estimate that the prevalence of apical periodontitis after endodontic infection may range between 12% to 80%. Collectively, generalized periodontitis and apical periodontitis thereby represent two of the most common chronic inflammatory diseases in humans; however, the pathological mechanism of apical periodontitis is less established. Oral chronic inflammatory diseases are associated with a subset of helper T cells expressing IL-17 (Th17 cells). Pathogenic Th17 cells are now recognized as a distinct Th17 subset, uniquely classifiable from homeostatic Th17 populations. These cells have been implicated as key drivers of disease pathogenesis in various systemic chronic inflammatory diseases. Similarly, an infiltration of Th17 cells has recently been associated with the severity of periodontal disease in response to oral microbial dysbiosis. Our preliminary studies with single-cell RNA sequencing confirm that periodontal T cells infiltrate the local inflammatory environment during pathogenesis of ligature- induced periodontitis in mice. Notably, these infiltrating T cells were found to highly express the major Ca2+ signaling via Ca2+ release-activated Ca2+ (CRAC) channel protein—ORAI1. ORAI proteins compose the core subunits of CRAC channels, which are essential for T helper cell differentiation and effector function. Recent studies demonstrate that the differentiation and pathogenicity of effector Th17 cells are highly sensitive to disruption of Ca2+ signaling. Although the transcriptional networks directly relying on CRAC channel activity to mediate differentiation and pathogenicity have yet to be fully elucidated, modulation of Ca2+ dependent mechanisms via ORAI have been proposed as an attractive therapeutic strategy for T-cell mediated diseases. Therefore, herein we seek to: 1) Establish the physiological role of ORAI1 in apical periodontitis. 2) Determine the ORAI-dependent transcriptional program in effector T cells. 3) Test the therapeutic potential of targeting ORAI to suppress apical periodontal T cell responses in oral inflammation. Outcomes of this investigation will help define the impact of oral Th17 cells and, more specifically, the pathological role of ORAI1 in microbial induced apical periodontitis. The candidate, Dr. Hasiakos, is an Endodontic Dental Specialty and PhD Program (DSPP) scholar pursuing an academic career in dentistry. The proposed project is directly relevant to his professional career development. The candidate identifies primary research mentors: Drs. Gwack and Srikanth—who discovered the role of CRAC channels in T cells and thus provide an ideal research training environment. The professional career development co-mentors, Drs. Nishimura and Kapila, are Co-PD/PI of the UCLA K12 DSPP that currently supports the candidate. Drs. Nishimura and Kapila are committed to guiding Dr. Hasiakos towards the completion of his PhD, application of translational methods in dentistry, and, ultimately, to his successful development as an academician.