Molecular Imaging to Identify Regulators of G-protein Signaling Proteins in Human Neutrophils and Their Role in Vasculitis

Project Summary/Abstract Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis (AAV) is a systemic autoimmune disease caused by pathogenic autoantibodies. The disease causes inflammation of small blood vessels in the kidneys, respiratory tract, and other organs leading to irreversible organ damage. Current immunosuppressive treatment strategies are often complicated by infections, adverse metabolic effects, infertility, and the development of malignancies. AAV is marked by a relapsing course in many patients. Unfortunately, there are currently no tools available to reliably predict the risk of disease relapse or response to treatment in individual patients. The Regulators of G Protein Signaling (RGS) are a family of proteins that inhibit the functional responses of G-protein coupled receptors (GPCR) by accelerating the hydrolysis of GTP to GDP. Alternatively, RGS proteins are known to regulate non-GPCR proteins, in particular the PI3K/Akt signaling axis. RGS proteins can interact with the p85 subunit of PI3K to facilitate the activation of Akt, though no study has probed the role of this interaction in the regulation of neutrophils. Because chemokines, leukotriene B4 (LTB4) and the activated complement component, C5a, play key roles in the onset and progression of AAV, it is important to identify and understand molecules and pathways that modulate the responsiveness of neutrophils to these molecules. Specific Aim 1 will determine the molecular interactions for RGS18 and RGS19 in human neutrophils. Specific Aim 2 will test the hypothesis that the C5a receptor blocker, Avacopan, blocks C5a- indued RGS signaling. The knowledge gained may ultimately allow for tailoring of treatment regimens to disease activity on an individual basis and provide important new insights into the organization of RGS proteins in neutrophils and new mechanisms that can be targeted to use as therapy in AAV and innate immunity diseases.