[F31] Mechanisms of Alveolar Epithelial Type 1 Cell Survival and Regeneration after Acute Lung Injury

Ente: National Heart Lung and Blood Institute

Scadenza: 2029-07-31

Importo max: $43,947

Paese: US

Descrizione

Acute respiratory distress syndrome (ARDS) is a life-threatening condition with no effective pharmacologic therapies. ARDS arises from damage to the alveolar epithelium, leading to fluid accumulation in the airspaces, impaired gas exchange, and respiratory failure. Alveoli are composed of Type 1 (AT1) and Type 2 (AT2) epithelial cells. While AT1 cells provide most of the gas exchange surface, they are thought to be especially vulnerable to injury. However, preliminary data from our lab suggest that AT1 cells can survive in mouse models of lung injury and in human ARDS. We found that AT1 cells upregulate Hbegf and Egfr, which encode the ligand HBEGF (Heparin-binding EGF-like growth factor) and its receptor EGFR (Epidermal Growth Factor Receptor), a pathway known to promote cell survival in other systems. We hypothesize that HBEGF/EGFR signaling promotes AT1 survival after injury. Additionally, in more severe injuries with AT1 loss, AT2 cells differentiate into AT1 cells. Our data suggest that Hbegf is also upregulated during this differentiation process, and that HBEGF may promote AT1 differentiation. Thus, our overall hypothesis is that HBEGF/EGFR signaling promotes AT1 survival and differentiation to preserve alveolar integrity and prevent ARDS. The two aims I propose are: Aim 1) Test the hypothesis that HBEGF/EGFR signaling promotes AT1 survival after lung injury. Aim 2) Test the hypothesis that HBEGF/EGFR signaling promotes AT1 differentiation during regeneration. This work will use transgenic mouse models, iPSC-derived alveolar epithelial cells, and both in vivo and in vitro assays to elucidate mechanisms of AT1 survival and alveolar repair. Understanding how alveolar integrity and regeneration are regulated will provide insight into potential therapeutic targets for ARDS, directly supporting the NIH mission to improve health and reduce the burden of human disease. The fellowship training will take place in Dr. Rachel Zemans’ lab at the University of Michigan, an outstanding environment for lung research. This fellowship will also provide comprehensive training in lung injury and regeneration research. Training activities will include in vivo mouse work, in vitro organoid cultures, molecular biology techniques such as qPCR, CRISPR/Cas9 genome editing, and western blotting. I will also employ flow cytometry, immunofluorescence staining, fluorescence in situ hybridization (FISH), and TUNEL staining for apoptosis, coupled with quantitative imaging analysis using QuPath software. I will also engage in regular mentoring, scientific presentations, career development workshops, and training in teaching and leadership. This training environment will prepare me to achieve my long-term goal of becoming an independent biomedical scientist. Istituzione: UNIVERSITY OF MICHIGAN AT ANN ARBOR PI: Rachel Evelyn Benedeck Progetto: 1F31HL173961-01A1

Settori: National Heart Lung and Blood Institute

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