CD38 modulation of NAD metabolism driving scleroderma pathogenesis

PROJECT SUMMARY/ABSTRACT In systemic sclerosis (SSc), fibrosis causes permanent functional damage in multiple organs. While non-resolving fibrosis in SSc has lethal consequences, its mechanisms are poorly understood and there is no effective treatment. Based on our exciting findings, we now propose the very novel hypothesis that fibrosis results from dysregulation of nicotinamide adenine dinucleotide (NAD) and nicotinamide (NAM) metabolism mediated by the enzymes CD38 (which breaks down NAD to NAM), and nicotinamide N-methyltransferase (NNMT), which couples cellular metabolic states to methylome changes and cellular reprogramming. Moreover, we propose that this multicellular CD38-NNMT metabolic axis represents a novel target for SSc therapy. Our preliminary results show that 1) expression of CD38 and NNMT are elevated in SSc patient biopsies, with these two NAD- metabolizing enzymes mapping predominantly to immune (CD38) or stromal (NNMT) cells, respectively; 2) genetic or pharmacological blockade of CD38 in mice is protective from fibrosis; 3) NAM, the main enzymatic substrate of NNMT that fuels its activity, is generated via CD38; and 4) NNMT is TGF-ß-inducible, and its inhibition abrogates fibrotic responses. Our novel paradigm, built upon these observations, implicates dysregulated NAD metabolism mediated via CD38 and NNMT in the pathogenesis of SSc. Specifically, we propose that elevated CD38 activity in SSc reduces NAD while generating NAM, both of which then drive fibroblast reprogramming via fueling NNMT activity and other mechanisms. This metabolic interplay between CD38-expressing and NNMT-expressing cells might be selectively targeted for fibrosis treatment. Despite our compelling observations, alterations in the key NAD metabolizing enzymes CD38 and NNMT, and their pathogenic roles, cellular sources and reciprocal interaction in a metabolic cellular network in SSc have never been investigated. We will therefore address these critical gaps in this proposal using a comprehensive experimental strategy deploying patient samples, novel engineered mice and disease models and pharmacological agents. In Aim 1 we will map CD38 expression in SSc patients and determine CD38's cell type-specific roles and mechanisms in fibrosis. In Aim 2 we will map NNMT expression in SSc patient biopsies and determine its cell type-specific pathogenic roles, mechanisms and interplay with CD38. The premise of our highly innovative proposal is that by elucidating the pathogenic roles and mechanistic links between CD38 and NNMT underlying dysregulated NAD metabolism in SSc, we will generate fundamental mechanistic understanding to guide discovery of entirely new treatments to reduce severity of SSc or delay onset of its deadly complications.