Targeting Aberrant Expression of Cytokines/Chemokines for an Inflammatory Nephritis Cure

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TARGETING ABERRANT EXPRESSION OF CYTOKINES/CHEMOKINES FOR AN INFLAMMATORY NEPHRITIS CURE PROJECT SUMMARY / ABSTRACT Lupus nephritis (LN) is an autoimmune, immune complex-mediated glomerulonephritis (GN), which is a frequent complication of systemic lupus erythematosus (SLE). Aberrant expression of inflammatory mediators and tissue injury characterize the early and later stages of LN. There is ongoing unmet need for therapies to attenuate the effects of early inflammation and the conversion of acute kidney injury to chronic damage in LN. We previously demonstrated that MG53, most commonly recognized as protein product of skeletal muscles, can mediate repair of damaged cell membranes, and can modulate cytokine expression in virally-infected macrophage. Of potential systemic importance, MG53 circulates and transgenic mice with a sustained elevation of circulating MG53 have a normal lifespan, but show enhanced regenerative capacity following a tissue injury. Mechanistically, MG53 interacts with tristetraprolin (TTP), a RNA binding protein that mediates mRNA 3’UTR degradation, an effect that maintains immune homeostasis by regulating the expression of many inflammatory cytokines and chemokines. We postulated that by manipulating circulating MG53 levels we will be able to attenuate renal inflammation and prevent tissue damage in LN. This proposal will use mouse genetics, tissue pathology, biochemical, molecular cellular studies and microscopy imaging to determine whether circulating MG53 can be sustained chronically to treat LN. Two specific aims are proposed. In Aim1, we will perform proof-of-concept studies to investigate the anti-inflammatory and tissue-repair effects of circulating MG53 in well-characterized lupus-prone mice. The feasibility of a novel DNA-modified microvesicle delivery system to achieve a stable elevation of circulating MG53 will be explored. In Aim 2, we will elucidate the underlying molecular mechanisms of MG53-mediated control of TTP signaling to modulate the expression of the inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1), as a model for how MG53 may be used to control cytokine expression in active LN.