OVERALL ABSTRACT Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplant (HCT) and prevents this curative therapy from wider application in cancer patients. This P01 consists of three projects and two cores and its goal is to significantly reduce GVHD by: (1) elucidating its basic biology; (2) developing new laboratory strategies to predict its long term outcomes; and (3) translating these insights into novel therapeutic strategies in Phase 2 clinical trials. Gastrointestinal (GI) GVHD is the target organ that is most resistant to steroid treatment and acute GVHD in the GI tract accounts for the vast majority non-relapse mortality. The focus on mechanisms of damage to the GI crypt during GVHD and enhancing its regeneration unifies all three projects during this cycle of the P01. Project 1 investigates the key bioenergetic pathways in intestinal stem cells (ISCs) that are altered during GVHD. Preliminary data have identified a profound defect in the key mitochondrial enzyme Succinate Dehydrogenase A (SDHA) that is specifically depleted by the T cell attack on intestinal epithelium during GVHD. Project 1 will analyze the role of SDHA in ISCs and will also evaluate SDHA expression in human GI biopsies in a collaboration study with Project 2. Project 2 also explores the regeneration of crypts by ISCs during GVHD, focusing on the key enzyme receptor-interacting protein kinase I (RIPK1) that controls the inflammatory cell death pathway. A collaboration with Genentech leverages their deep expertise in this field to explore RIPK1 biology in animal models and human samples. Project 2 shares a subaim with Project 1 to investigate the interactions of SDHA with the RIPK1 pathway in ISCs during GVHD. Project 3 translates insights from the preclinical projects into two highly innovative clinical trials. The first trial will test a Genentech RIPK1 inhibitor in a Phase 2 trial. The second trial uses novel real- time monitoring with serum biomarkers to identify a group of patients with minimal GI crypt damage who can be safely treated with much lower doses of steroids. This P01 thus represents a translational progression of exploration of GVHD biology from basic through translational models to clinical trials that leverage multiple synergies between projects with the goal to accelerate transformative therapeutic strategies for GVHD patients.