ABSTRACT Sjögren’s Disease (SjD, formerly known as Sjögren’s syndrome) is a common systemic autoimmune rheumatic disorder second only to rheumatoid arthritis in prevalence. It primarily affects salivary and lacrimal glands through lymphocytic infiltration and autoantibody-mediated inflammation, resulting in significant morbidity. Approximately one third of SjD patients have extraglandular involvement and have a remarkably elevated risk for lymphoma. Unfortunately, limited progress has been made in addressing the many unmet needs in SjD. Confirmatory diagnosis is multidisciplinary in nature and often results in significant delay. Scant therapeutic options exist outside of symptom management, and results from recent clinical trials have been disappointing. Thus, a better understanding of the pathogenetic mechanisms of disease is critical, and can be achieved using a de- and re-construction approach. Central to this goal, is the need for deeply characterized patients with SjD. The multidisciplinary Sjögren’s Team for Accelerating Medicines Partnership (STAMP) is ideally poised to assemble this resource. The team’s expertise includes autoimmunity-focused molecular biology, genetic, and epidemiologic/clinical research, and a remarkable track-record in establishing large cohorts of participants with stored biospecimens and exquisitely detailed phenotypic characterization. In addition to recruiting new participants, the existing cohorts will provide the unique opportunity to perform 10 to 15-year follow-up of previously evaluated SjD participants. Our proposed Disease Team (DT) is strategically positioned to apply cutting-edge technologies to interrogate the tissue and systems biology of SjD to identify therapeutic pathways and targets, with the following aims: 1) Planning Phase: Develop a 5-year scientific research agenda and SOPs for phenotyping SjD patients in collaboration with other AMP DTs and Technology and Analytics Cores (TACs). Design standardized protocols to recruit, enroll, collect biospecimens and perform deep phenotyping of observational cohorts of SjD and controls. Identify research priorities for SjD to better understand the molecular and phenotypic heterogeneity and natural history at both tissue and cell levels; 2) Pilot Phase: Calibrate clinical assessments and sample procurement across recruitment sites and evaluate SOPs. We will work closely with other DTs and TACs to a) finalize SOPs and implement them at all sites; b) leverage our multidisciplinary expertise to initiate the deconstruction-reconstruction of SjD via preliminary analyses of molecular and clinical data; 3) Scale up Phase: Increase participant recruitment and work with TAC to molecularly deconstruct and reconstruct SjD. Standardized protocols implemented across sites will enable STAMP to interrogate the tissue and systems biology of SjD using deep sequencing and other cutting-edge technologies, to better understand 1) the pathogenesis of SjD and identify therapeutic t...