Salivary gland dysfunction is a significant medical problem caused by injury or disease, including Sjögren’s Syndrome (SS), a chronic inflammatory autoimmune disease characterized by hyposalivation and lymphocytic infiltration of salivary glands (i.e., sialadenitis). Treatments for hyposalivation are limited and deemed to be inadequate. Thus, development of effective SS treatments is essential. In chronic sialadenitis, alarmins produced locally in salivary glands promote accumulation of immune cells, tissue degeneration and glandular fibrosis that exacerbate SS pathogenesis and hyposalivation. Published and preliminary data from the Principal Investigator’s lab show that localized release of cytoplasmic nucleotide alarmins, such as ATP, from damaged cells activates the P2X7 receptor (P2X7R) signaling pathway to promote hyposalivation and sialadenitis in SS mouse models, whereas P2X7R antagonism normalizes saliva production and reduces sialadenitis. Previous work of the Co- Investigators has established sialendoscopy as a promising therapy for SS-associated hyposalivation, in which salivary gland ducts are endoscopically irrigated to dilate occlusions. To translate our (pre)clinical findings into an effective therapeutic intervention, we propose to use contrast-enhanced ultrasound and sialendoscopy (CEUSS) with gas-filled microbubbles to dissolve ductal occlusions combined with local and systemic application of the P2X7R antagonist AZD9056 (obtained from Phoenicis), in an anticipated U01 phase I/IIa clinical trial with human SS patients to reduce sialadenitis and enhance saliva production. This approach will offer unprecedented possibilities to reduce the burden to patients with SS, while achieving intra-operative diagnostic salivary gland imaging and evidence of therapeutic efficacy. The anticipated U01 phase I/IIa trial will assess safety, maximum tolerated dose, pharmacokinetic and pharmacodynamic properties and clinical efficacy of AZD9056 in the first dose-escalation and cohort-expansion trial with primary SS patients. The trial will determine whether the combination of intraductal and systemic AZD9056 administration in SS patients inhibits cellular mechanisms underlying SS using clinical biospecimens. R34 Specific Aim 1: Develop regulatory plan for intraductal and systemic AZD9056 in SGs of SS patients. R34 Specific Aim 2: Develop clinical protocol, budget and multinational clinical data management plan for systemic and intraductal AZD9056 co-administration in SS patients. R34 Specific Aim 3: Develop protocols for SS patient biospecimens to determine effects of AZD9056 on mechanisms of SG dysfunction in SS patients.