Project Summary Allogeneic hematopoietic cell transplantation (HCT) is a long-established therapy for blood malignancies. The therapeutic benefit and potential cure achieved by HCT is mediated by the graft-vs-leukemia (GVL) effect that is derived from donor immune system. However, the full recognition of the GVL effect has been hampered by disease relapse and graft-versus-host disease (GVHD). The overarching objective of the research projects in this application is to better understand the complex pathophysiology of chronic GVHD, the mechanisms leading to fibrosis and lung injury, and to develop therapeutics targeting the major pathways leading to the common clinical manifestations of chronic GVHD. More specifically, Project 1 will identify immune networks that characterize patients who will develop cGVHD and interrogate mechanisms of response to various treatments for chronic GVHD; Project 2 will be dedicated to develop into bronchiolitis obliterans and lung fibrosis to identify new therapeutic agents to treat lung chronic GVHD; and Project 3 will perform a phase II clinical trial of a ROCK2 inhibitor to treat lung cGVHD, identify the cellular target of immunologic attack in bronchiolitis obliterans syndrome (BOS) using lung organoids, and identify the antigenic determinants of immune attack in BOS. Project 1 involves various translational studies to identify a immunologic signature for cGVHD, Project 2 involves animal studies and Project 3 involves both a clinical trial as well as translational studies to achieve the overarching goal of this application. The primary objective of the Biostatistics and Data Management Core (Core 3) is to provide statistical collaboration for all investigators involved in this Program Project. This includes collaboration with project investigators in the design of clinical trial and laboratory studies, analysis of clinical and laboratory data and to establish correlations of clinical outcomes with laboratory results, and participate in manuscript writing in all Projects. Core 3 will also provide centralized mechanisms to assure the timely and complete capture of all clinical data in this Program Project. This includes collection and maintenance of necessary clinical information, data management support, quality control for clinical data, and oversight of clinical trial operations to ensure that all data elements required by each protocol are collected in timely fashion; and where necessary, design of research procedures and databases to allow blinded laboratory assessments and later integration with patient- level data for analysis.