ABSTRACT The Blood and Marrow Transplant Program at the University of Michigan (Ann Arbor, MI) has made major scientific contributions to the BMT CTN over the past 15 years. The University of Michigan is now partnering with Indiana University (Indianapolis, IN) and the Karmanos Cancer Institute (Detroit, MI) to participate as a Core Clinical Consortia for the BMT CTN Network. Collectively, our 3-member consortia currently perform over 750 transplants/year, including 300+ allogeneic and 85 pediatric transplants annually. Our consortia has a strong emphasis in non-malignant disorders, with over 1500 patients with sickle cell disease currently followed at consortium sites, and 46 transplants for sickle cell disorders collectively performed to date. Our consortia is likewise strong in pediatric disorders, with each site affiliated with a Children's Hospital on their respective campus. We have a track record for translating early phase, clinical trials to multicenter studies, have comprehensive biorepositories as foundations for our programs, and have physician scientists (Dr. Pavan Reddy, Dr. Hal Broxmeyer, Dr. Sophie Paczesny) with a history of academic success. Our research strategy will propose a new paradigm, one that focuses on the inhibition of damage response pathways as a potential mechanism to prevent the organ toxicity associated with conditioning and GVHD. The release of damage associated molecular patterns (DAMPs) from non-specific host tissue injury is a consequence of pre-HCT conditioning. DAMPs provide crucial initiating signals that lead to activation of antigen presenting cells (APC), triggering potentially lethal inflammatory responses. Based upon pre-clinical work from the laboratory of Pavan Reddy (PI: Scientific Lead), and a pilot study currently being run at consortia sites, we are now proposing a randomized, placebo controlled trial of a damage response modifier, CD24Fc, in unrelated donor transplant recipients. Due to its long half-life, the agent is only required to be given only once during transplant, on day -1 pre-transplant. The primary endpoint will be day 100 acute GVHD. Secondary endpoints will examine the effect of CD24Fc administration on DAMP's dependent inflammatory signaling post-HCT. We anticipate that this trial will not only mitigate the onset and severity of GVHD in recipients, but will advance our understanding of the biology and clinical importance of regulating key damage response pathways after HCT. Our consortia is committed to advancing the scientific agenda of the BMT CTN, and feel this research strategy will provide new insights into reducing both GVHD and regimen related toxicities associated with HCT. Our three centers are not just close in geographic proximity, but are closely aligned to address key transplant issues within the CTN.