Systemic sclerosis (SSc; scleroderma) is a complex autoimmune disease without a cure or an effective therapy for the many devastating aspects of disease. Mouse models do not recapitulate all features of SSc, mandating human studies for understanding this complex pathogenesis. The median survival is ~11 years after SSc diagnosis and the estimated national hospital costs related to SSc exceed 275 million yearly. SSc affects 250 per 1 million people in the US, with a ~3-4 time greater prevalence among Veteran’s Health Administration patients. The pathogenesis of SSc is characterized by immunological abnormalities, vascular changes, notably in the microvasculature, and fibrosis, yet both the cause and effect of these mechanisms within the gastrointestinal tract (GIT), which is the most common extra-cutaneous organ system damaged in SSc, is unknown. Our previous work supported by I01 CX002111-01 “Systemic sclerosis (SSc) vasculopathy: Improved clinical monitoring and treatment” discovered that that both large artery (i.e., brachial artery), as well as microvascular (i.e., arterioles and capillaries) endothelial dysfunction is a critical feature of SSc. A dysfunctional endothelium leads to increased vascular permeability, greater tissue immune cell infiltration, blunted angiogenic capacity and impaired vascular reactivity and tissue blood flow. While we showed that acutely we could improve this vascular dysfunction, clinical interventions are limited by trial design issues and are greatly improved by models that specifically study the mechanism of disease. We identified a novel method for quantifying microvascular change in the oral cavity (sublingual videomicroscopy) that correlates to GIT symptoms in SSc. This sublingual videomicroscope measures the glycocalyx, which maintains homeostasis of the vasculature, including controlling vascular permeability and microvascular tone, preventing microvascular thrombosis, and regulating leukocyte adhesion. In the first specific aim of our proposed study, we will perform a natural history study of the glycocalyx, its relation to GIT patient reported outcomes (PRO) and end-stage vasculopathy features, including digital ulcers (DU), pulmonary hypertension (PH), scleroderma renal crisis (SRC), calcinosis, and telangiectases. In the second specific aim of the proposed study, we will develop a novel model to further study these end-stage vasculopathy features (DU, PH, SRC, calcinosis, telangiectases, and severe GIT symptoms) in Veterans with SSc. We will generate endothelial cells (EC) from inducible pluripotential stem cells (iPSC) created from their blood and age- frequency and sex matched healthy controls. The main research objective of this project is to build upon our current clinical research program for our Veterans with SSc that has identified important in vivo aspects of SSc vasculopathy and its relation to PRO. The over-arching goal of this project renewal is to define SSc-GIT vasculopathy through serial ...