Abstract This revised R03 award will assess the novel hypothesis that the alternative complement pathway is a critical mediator and potential therapeutic target for connective tissue disease associated pulmonary arterial hypertension (CTD-PAH). This work will allow Dr. Benjamin Korman, a current NIAMS K08 awardee, to develop a new area of research and develop independence. The studies described build upon exciting preliminary data characterizing TNF transgenic mice (TNF-Tg) as a novel model of CTD-PAH. Specific aim 1 assesses the ability of genetic ablation of complement to prevent the PAH phenotype by crossing TNF-Tg mice with complement component 3 (C3) deficient mice. To determine the specificity of this effect to CTD-PAH, the effect seen will be compared to WT and C3 deficient mice with pulmonary hypertension induced by the Sugen- hypoxia model. Specific aim 2 will further explore complement’s mechanistic role to assess how TNF and complement in pulmonary artery endothelial cells regulate adhesion molecules and apoptosis, whether classical or alternative complement factors are required for these phenotypes, and assess how endothelial cell derived complement may alter macrophage phenotypes. In specific aim 3, we will use fusion-protein complement inhibitors CR2-Crry (pan-complement) and CR2-fH (alternative pathway specific) to assess whether treatment of TNF-Tg mice with complement inhibition can reverse established PAH and whether this is specific to the alternative pathway. This proposal will provide critical preliminary data which will form the basis for an R01 award in which Dr. Korman will study the pathological role of the complement cascade in CTD-PAH and associated vasculopathy using patient materials and animal models.