This is a K08 award application for Dr. John Li, a pediatric critical care physician at UCSF. Dr. Li's long-term goal is to improve the health and outcomes of patients with acute lung injury (ALI) by identifying key therapeutic targets within the adaptive immune response that contribute to the pathogenesis of ALI. ALI is a devastating clinical syndrome with no effective therapies. Although research in ALI has focused on the innate immune system, recent studies are beginning to shift the paradigm of ALI to include an important role for the adaptive immune response. The central hypothesis of this proposal is that an adaptive immune response driven by Th17 cells is important in disrupting the alveolar-capillary barrier. The hypothesis has been formulated on the basis of strong preliminary data showing: (1) mice defective in generating Th17 cells are protected from lipopolysaccharide (LPS)-induced ALI;(2) antibody blockade of IL-17A, a member of the IL-17 cytokine family, protects mice against alveolar vascular permeability changes in experimental ALI;(3) recombinant IL-17A stimulates increased protein expression of ROCK1, a downsteam effector of RhoA signaling, and increases permeability of pulmonary endothelial cell monolayers;and (4) lung epithelial water transport is impaired by IL-17A. Guided by strong preliminary data, the central hypothesis will be tested by pursuing three specific aims: (1) Determine the cellular source of pathogenic IL-17 and trafficking of IL-17 secreting T cells into the alveolar space in experimental ALI;(2) Identify the molecular mechanism of IL-17A mediated disruption of lung endothelial barrier function;and (3) Determine the effects of IL-17A on lung epithelial barrier function and the mechanism of IL-17A mediated impairment of vectorial fluid transport in the lung epithelium. This approach is innovative because it represents a new and substantive departure from the status quo, namely the focus on the adaptive immune response in ALI. Specifically, we aim to elucidate the role of Th17 cells in the pathogenesis of ALI. The proposed research is significant because with this knowledge, we can next test whether blocking IL-17A or its downstream pathways by pharmacological agents can decrease the inflammation and injury caused by Th17 cells. To achieve these goals, Dr. Li has assembled a mentoring team comprised of a primary mentor, Dr. Dean Sheppard, a highly regarded researcher in integrin biology and pulmonary disease with an outstanding record of training independent scientists, and two co- mentors, Dr. Michael Matthay, a renowned expert in the field of ALI, and Dr. Joseph McCune, a leader in immunology and experimental medicine. Furthermore, a detailed curriculum of didactic and hands-on courses, scheduled participation in scientific conferences, and professional development activities has been designed for Dr. Li's career development. This research will form the basis for translational studies in pediatric patients with ALI, to be proposed in an R01 grant application before the end of the K08 award period.
The results of these studies will fill important gaps in our understanding of the role of the adaptive immune system, specifically Th17 cells, in acute lung injury. These findings can lead to novel new treatments to improve the outcome of critically ill patients with acute lung injury.