Project Summary: Allogeneic hematopoietic stem cell transplantation (HCT) is an effective treatment for hematological malignancy, however it is associated with significant complications limiting its application. Chronic graft-versus- host disease (CGVHD) is the leading cause of long-term morbidity and mortality following HCT and recent advances have failed to make a significant impact on its frequency or severity. The mechanisms of the development and evolution of CGVHD have not been clearly defined making the design of new therapeutic approaches aimed at preventing or treating the disease challenging. Flow cytometry and gene expression profiling have become valuable tools to interrogate complex disease states and define the molecular changes that occur during the development of disease. Utilizing these approaches to identifying the mechanistic drivers of CGVHD would aid significantly in our understanding of the disease and help elucidate targetable pathways to alter its natural history. To identify the mechanisms driving GVHD, our group has developed a systems biology approach that combines flow cytometry with gene expression analysis. The proposed research project will apply these supervised and unsupervised approaches to determine the molecular signature of T and B cells linked to the development and evolution of CGVHD. The proposed work will utilize the highly curated biorepository of our clinical trial. The randomized, placebo-controlled phase II clinical trial is investigating abatacept (CTLA4-Ig) as a novel GVHD prevention agent and will provide detailed clinical data that will be linked to the biologic samples. Aim 1 will seek to identify the T and B cell genes and pathways associated with the development and evolution of CGVHD and determine if the molecular changes can be used to risk-stratify patients at day 100. Aim 2 will seek to address the impact of abatacept on CGVHD by identifying the T and B cell genes and pathways associated with CGVHD in abatacept treated patients and compare the associated molecular changes to the changes that occur in patients with CGVHD not exposed to abatacept. Completion of these aims will add significantly to our understanding of the development and evolution of CGHVD and hopefully provide the data necessary to create a risk-adapted approach to CGVHD prevention. It will also provide insight into the mechanism of action of abatacept and reveal the means of the breakthrough CGVHD that occurs. Dr. Watkins has identified an exceptional mentoring team and in combination with his experience and career development plan is poised to succeed with his proposed research plan. Dr. Watkins will benefit greatly from the supportive research environment of Emory University and the formal training in clinical trial methodology and bioinformatics will solidify his skills in clinical research. The structure and support provided by the K23 will facilitate Dr. Watkins? translation into a successful independent physician scientist and a leader in the field of CGVHD.