Cellular and molecular determinants of an injury-associated capillary endothelial cell state during acute lung injury and regeneration - PROJECT SUMMARY/ABSTRACT This proposal describes a five-year training plan for the development of an independent research career focused on studying how endothelial immune signaling affects the lung’s response to viral injury. The applicant strives to understand how endothelial cells coordinate immune responses early after influenza infection and how a novel population of injury-associated capillary endothelial cells is regulated at sites of persistent lung injury late after infection. The applicant is a Postdoctoral Fellow of Medicine in the Division of Pulmonary, Allergy and Critical Care at the University of Pennsylvania. He has PhD training in molecular microbiology with a focus on using bioinformatic approaches to understand how populations of cells interact with the adaptive immune system. The goals of this award are for the applicant to gain additional expertise that will help him pursue a career as an independent investigator with a focus on endothelial-immune interactions. The mentor for this award is Dr. Edward Morrisey, an internationally recognized leader in lung regeneration with an outstanding training record. An advisory committee comprising scientists with expertise in domains related to this proposal will support the goals articulated in the training plan. The applicant will benefit from the unreserved support of his institution as well as the unparalleled mentoring, resources, and scientific community at the University of Pennsylvania. The applicant’s preliminary data define how the pulmonary endothelium responds to influenza infection by upregulating genes involved in immune responses. After resolution of the infection, a novel population of capillary endothelial cells is observed adjacent to immune cells in sites of persistent injury, exhibiting increased expression of genes involved in immune signaling. The proposed studies will address the hypothesis that pulmonary endothelial cells coordinate the early antiviral immune response and are maintained in an aberrant inflammatory state late after infection at sites of dysplastic tissue repair. This will be accomplished through experiments in two Specific Aims incorporating mouse genetic knockout models, lineage tracing, immunofluorescence imaging, and spatial transcriptional profiling.The first aim seeks to define the role of two important immune signaling pathways that are expressed in lung endothelial cells and upregulated during inflammation. The second aim investigates the molecular and cellular pathways that give rise to and sustain inflamed capillary endothelial cells late after lung injury. The applicant has established a career development plan that complements his current strengths with additional training in immunology, physiologic measurements of lung disease, and advanced bioinformatics. These training goals will be integrated with professional development activities, additional coursework, and input from his Advisory Committee to help the applicant establish an independent basic science research program focused on endothelial-immune signaling in viral injury and lung regeneration. This work addresses a needed area of investigation and has a high potential for therapeutic impact in patients recovering from lung injury.
