This dissertation proposes a potential intersection between therapeutic targeting of both oral and systemic inflammatory conditions. Three chapters are presented, beginning with a clinical study to explore the demography of apical periodontitis (AP). A summary of the relevant background information for the core topics of this collective work is provided in the Introduction. Chapter 1 highlights variable trends in the prevalence of endodontic disease and treatment observed between various systemic health conditions. Chapter 2 and Chapter 3 introduce a comprehensive investigation into the role of calcium signaling via ORAI channels in T-cell function(s) and their candidacy as a therapeutic target.Chapter 1: Apical Periodontitis and Systemic Health– A Clinical Study and Focused Review We initiated a retrospective demographic study to examine the prevalence of AP in a patient population with varying systemic health histories. Three evaluators completed retrospective analysis 227 patient charts. Our study found a 44% overall prevalence of AP. Potentially clinically relevant trends in the rate among patients with diabetes, cardiovascular disease and hypertension were also noted. These data support a potential link between systemic health and AP, warranting further investigation. We postulate that differences in the host immune competence attributed to systemic conditions or their management may underlie the observed trends. Chapter 2: Transient Calcium Block Attenuates T-Cell Pathogenicity Given the importance of Calcium Release Activated Channels (CRAC) in T-cell function and overall host immunity, we sought to validate modulation of their function as a therapeutic target. We first characterized a novel triple knock-out system of ORAI homologues to mimic pharmacologic block of CRAC channels. Unexpectedly, these mice exhibited spontaneous inflammatory bowel disease (IBD), underscoring a critical role for CRAC channels in maintaining T-cell homeostasis. However, using a transient pharmacologic CRAC channel blocker (BTP2), our work demonstrated that Th17 cells, particularly pathogenic subsets, are highly sensitive to the temporal disruption of CRAC channel function during differentiation. This transient blockade resulted in reduced cytokine production and long-lasting changes in their transcriptomic and metabolic profiles, suggesting that transient inhibition of calcium influx via ORAI channels may provide therapeutic benefits. Chapter 3: Temporal ORAI Block Uncouples Novel Mechanisms to Regulate MYC and Protects Mice from Autoimmunity. We next aimed to uncover the calcium sensitive molecular mechanism(s) responsible for long-lasting changes in pathogenicity after temporal disruption of CRAC activity during T-cell differentiation. Utilizing a conditional genetic knockout system (Orai1fl/fl; Cd4Cre mice), we identified candidate transcription factors regulated by CRAC channel function. RNA sequencing analysis suggested that inhibition of calcium influx during the early stages of Th17 differentiation critically regulates MYC activity via the MXD family of transcription factors. Overexpression of MYC restored cytokine production in cells treated with the CRAC channel blocker, while overexpression of MXD1, a MYC antagonist, inhibited cytokine production. Finally, in vivo studies using experimental autoimmune encephalitis (EAE) models demonstrated that targeting ORAI channels either genetically or pharmacologically ameliorates disease severity by reducing Th17 driven inflammation in the central nervous system (CNS). Conclusion Demographic studies to dissect associations between apical periodontitis and systemic health are important to inform clinical care. Our clinical study identified several potentially relevant trends in patients with various common systemic health conditions. Altered host immune functions attributed to such diseases may underly their association with susceptibility to infection-induced apical periodontitis. Our research supports the therapeutic potential of modulating calcium signaling via ORAI channels for the management of chronic inflammatory diseases. Future studies should explore and further validate the therapeutic application of CRAC channel inhibitors to a broader range of systemic co-morbidities, including oral inflammation.