Generation of Endothelial Cell Memory in Inflammatory Vascular Disease

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Summary of the Research Project: Pulmonary arterial hypertension (PAH) is a life-threatening disease with no cure characterized by severe lesions in the pulmonary vessels due to hyperproliferation of vascular cells, including endothelial cells. The primary cause of these lesions is largely unknown, but several studies indicate they result from chronic inflammation, such as that caused by Schistosoma mansoni infection. ~10 million people infected with S. mansoni develop PAH (Sch-PAH). Thus, a better understanding of how the infection promotes the formation of vascular lesions will provide insights for identifying novel molecular targets for PAH treatment. Recently, we reported that endothelial cells that survive to chronic lung injury, show reduced expression of the anti-proliferative scaffolding protein caveolin-1 (Cav-1) and elevated response to pro-fibrotic TGF-β signaling. Activation of TGF-β requires recruitment of Th2 cells into the lungs, which in turn expands Cav-1 depleted endothelial cells and promote PAH. Although it is unknown how Cav-1-depleted endothelial cells contribute to Sch-PAH, our preliminary data indicate enhanced expression of inhibitor of apoptosis protein 2 (c-IAP2) may participate in this process. In line with this observation, data suggest that S. mansoni-primed endothelial cells retain in vitro a memory of the in vivo infection. Specifically, this memory is characterized by impaired function of the death associated receptor P2X7, which is controlled by Cav-1 expression. Thus, I hypothesize that while S. mansoni infection leads to lung endothelial cell death and secretion of c-IAP2, recipient cells generate a long- lasting survival memory required for endothelial-immune cell crosstalk and the development of Sch-PAH. Candidate & Institutional Environment: Dr. Oliveira is Junior Faculty at the University of Illinois at Chicago (UIC). She earned her Ph.D. in Immunobiology and M.Sc. in Pharmacology from the Federal University of Rio de Janeiro, Brazil. As a Latin woman, she grew up surrounded by different cultural backgrounds, and thus, learned how diversity is a crucial part of the human experience and existence itself. Dr. Oliveira’s career development plan combines the knowledge and technical expertise from her graduate and post-graduate training with novel methodologies and research subjects to build up a unique trajectory toward becoming a fully independent investigator. Specifically, Dr. Oliveira proposes advancing her leadership skills, strengthening her inter-institutional network, providing and organizing lectures inside and outside of her institution, and further engaging in mentoring and student evaluation. To achieve these goals, Dr. Oliveira built a team with distinguished Professors from the areas of expertise needed for both the scientific and professional success of her career development plan. In terms of the environment, Dr. Oliveira is located in an acclaimed research institution dedicated to discovering and distributing knowledge. Thus, along with her professional growth, Dr. Oliveira plans to promote the growth of the academic community as a whole by engaging all voices into an inclusive and creative environment required for continuous scientific progress and institutional excellence.