R01AI162616

RNA Binding Proteins in End-Organ Autoimmune Pathology

IL-17 and Th17 cells are dysregulated in many pathologic auto-inflammatory conditions. Antibody-mediated glomerulonephritis (AGN) occurs when unchecked inflammation is triggered by autoimmune antibody complexes that deposit in glomeruli and lead to kidney damage. This condition can be observed in diseases such as Goodpasture disease, ANCA vasculitis, etc. Although the initiators of autoantibody-mediated pathology differ, the terminal events in end organ kidney damage have many common hallmarks, and the fundamental immunology of this process is still not well understood.

Accumulating evidence from our groups and others have convincingly demonstrated a role for IL-17 in driving the pathogenesis of AGN in humans and in mouse models. Excessive autoimmune pathology can be caused by hyper-production of cytokines from T helper cells or by over-exuberant cytokine signaling. Therefore, in principle, molecules that influence IL-17 signal transduction have the potential to be viable targets for therapy in settings where this cytokine is a disease driver.

In probing the fundamental mechanisms that mediate IL-17-dependent signaling, we identified two novel RNA binding proteins (RBPs) that contribute significantly to the pathogenesis of AGN in vivo. These RBPs are downstream of IL-17, and their activities in the IL-17 pathway are interconnected through the regulation of CCAAT enhancer binding protein (C/EBP) transcription factors. In turn, C/EBPs mediate IL-17-dependent effectors that promote renal inflammation, including lipocalin-2, neutrophil-recruiting chemokines, and feed-forward activators of Th17 differentiation such as IL-6.

Our central hypothesis is that IL-17 promotes inflammation through post-transcriptional regulation of downstream mRNAs that drive renal pathology in AGN. This proposal aims to evaluate the molecular mechanisms by which these RBPs act and their specific physiological functions in the setting of AGN.

University Of Pittsburgh - Of The Commonwealth System Of Higher Education

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93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Pittsburgh, Pennsylvania 152133203 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 401% from $633,244 to $3,169,819.