Project 1: Mitochondrial Bioenergetics and Metabolism of ISCS in GVHD

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PROJECT 1 ABSTRACT The overarching goal of this P01 is to develop non immunosuppressive strategies to prevent and treat gastrointestinal (GI) GVHD, which remains the major cause of morbidity and mortality. In working toward this goal in the current cycle, we focused on understanding the role of target tissue intrinsic mechanisms of resilience in regulation of GVHD. We uncovered an exciting, previously unknown role for metabolic aberrations in the intestinal epithelial cells (IECs) and their regulation by microbial metabolites in regulating the severity of GI GVHD. Work published in the current cycle identified a key role for IECs in the protection mediated by short chain fatty acids such as butyrate and propionate. Unpublished preliminary data generated by us identified a profound defect in mitochondrial complex II (MC II), specifically reduction of its component, succinate dehydrogenase A (SDHA), in IECs that contributed to greater severity of GI GVHD. These studies have identified a key role for SDHA in bulk IECs, which is made up of a number of distinct subsets. Emerging data in recent years suggest that quantitative loss of only a few key IEC subsets, specifically Lgr5+ intestinal stem cell (ISCs) and Paneth cell subsets are critical features of severe GI GVHD. But the cell intrinsic pathways that are critical for their function and maintenance remain unknown. Our new preliminary data demonstrate that the mitochondrial metabolic defect, reduction of SDHA component of the mitochondrial complex II (MC II), in the bulk IECs, is also observed in the ISC subset. In this project, we will build on these exciting and seminal preliminary observations and explore the role of mitochondrial metabolic and bioenergetics functions in the biology of ISC and its contribution to tissue resilience in mitigating the severity of GI GVHD. Specifically, we will test the central hypothesis that the cell autonomous deficiency of mitochondrial complex II component, SDHA, in the host Lgr5+ ISCs regulates its metabolism and amplifies GI GVHD. The specific aims are: Specific Aim 1: To determine the functional relevance of mitochondrial complex II component (SDHA) in host Lgr5+ ISCs to GI GVHD and Specific Aim 2: To determine the impact of mitochondrial complex II SDHA deficiency on the biology of Lgr5+ ISC. Collectively, our proposal will probe the previously unexplored biology of ISC intrinsic pathways that are critical for regulation of GI GVHD severity. Importantly, it is thematically synergistic with other projects in the P01 with a focus on ISCs, is grounded by novel preliminary data, and is supported by state of the art Cores. If successful, our proposal will provide seminal insights into fundamental biology of ISCs will provide novel targets to mitigate GI GVHD without adding more immune suppression.