PROJECT SUMMARY/ABSTRACT The broad objectives of this K08 proposal are two-fold: 1) to facilitate development of the necessary skills that will allow the candidate to achieve her long-term goal of becoming a successful physician-scientist focusing on determinants of recovery from viral pneumonia in aged hosts, and 2) to investigate the mechanisms that direct the Tregs to orchestrate resolution of severe lung injury throughout the lifespan. The candidate and her mentors have designed a detailed training plan tailored to the candidate's specific needs and goals. The plan includes a rigorous research component that will afford the PI new knowledge and research skills to better examine the links between a critical immune cell population and the endothelium during recovery from viral pneumonia. The proposal concerns viral pneumonia, specifically influenza-induced lung injury, its clinical counterpart the acute respiratory distress syndrome (ARDS) and how they both disproportionately affect the elderly population. Despite decades of dedicated research, there are only a few anti-viral therapies with limited efficacy to manage severe viral pneumonia. Tregs have been shown to decrease inflammation and promote tissue repair in diverse murine models of lung injury. Tregs also increase in the lungs of patients with ARDS, suggesting that they may play a role in the human adaptive immune response to lung injury. However, the specific mechanisms that cause Tregs to execute their pro-repair program following lung injury remain unknown. Our preliminary data shows that the youthful reparative Treg cell program following influenza-induced lung injury is dominated by biologic processes linked to the development and repair of blood capillaries. This reparative program is lost in aged hosts in a cell- autonomous manner. Thus, we hypothesize that aging results in Treg cell-specific downregulation of important pro-angiogenic factors expression such as VEGFA, leading to impaired alveolar endothelial repair and recovery from viral pneumonia. The long-term goal of the proposal is to identify novel small molecule- and cell-based therapeutics to control inflammation and promote tissue repair in our increasingly older population. To test this hypothesis, we propose the following Specific Aims: 1) determine whether age-related alterations in the pro- endothelial repair function of Tregs results from cell-autonomous or microenvironmentally-driven changes, 2) determine whether Treg cell-generated VEFGA is necessary and sufficient to restore the pro-endothelial repair function present in youth that is lost with aging, and 3) determine whether age-related VEGFA expression in alveolar Tregs in bronchoalveolar lavage fluid is associated with 30-day mortality in patients with severe viral pneumonia. We will use standard techniques to assess severity of lung injury, endothelial repair, heterochronic (age mis-matched) adoptive Treg cell transfer, multiple transgenic murine strains for ...