ABSTRACT The goal of this K24 is to provide support to allow Dr. Ashare to spend an additional 25% of her time mentoring junior physician scientists in patient-oriented research on inflammatory lung disease. This K24 will provide the opportunity for Dr. Ashare to expand her program in patient- oriented translational research, integrate new physician scientists and PhD scientists into her research program, and allow for additional protected time so she can mentor additional trainees. In addition, with the help of her senior advisory committee, she will also use this time to improve her own mentoring skills. This K24 describes two aims that involve patient-oriented translational research using primary lung macrophages obtained from human subjects. Each Aim will serve as an individual project for a new trainee. Aim1 exploits preliminary findings that macrophages isolated from different regions of the lung are metabolically different and will specifically investigate the impact of increased glycolytic metabolism in upper lobe macrophages on the generation of inflammation. This aim will also determine the role of succinate accumulation in the generation of the macrophage inflammatory response. Based upon our data demonstrating that there are phenotypic and genotypic differences in Pseudomonas aeruginosa isolates from different regions of the CF lung, Aim 2 will test the hypothesis that regional P. aeruginosa isolates differentially stimulate lung macrophage immune responses and exhibit different responses to extracellular succinate. These two independent but complementary aims will allow new trainees to pursue translational patient-oriented research projects that will lead to a greater understanding of host-pathogen interactions in the CF lung.

PROJECT NARRATIVE The goal of this K24 is to provide support for Dr. Ashare to spend an additional 25% of her time mentoring junior scientists in patient-oriented research on inflammatory lung disease, as well as additional time developing her own mentoring skills. This innovative and potentially paradigm shifting research in human subjects is important for public health because understanding the mechanisms underlying regional development and progression of inflammatory lung disease will have a critical impact on investigations of novel therapeutic interventions for lung diseases such CF. Furthermore, the proposed research is germane to the NIH’s mission focusing on discoveries related to human disease pathogenesis and translation of these studies to clinical medicine.