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Regulation and Role of Forkhead Box F1 in lung injury

Acharya, Anusha
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1712911854126192

Abstract Details

2024, PhD, University of Cincinnati, Medicine: Cancer and Cell Biology.
The transcription factor Forkhead Box F1 (FOXF1) plays a critical role in lung angiogenesis during embryonic development and lung repair after injury. In adult lungs, it is highly expressed in endothelial cells, fibroblasts and pericytes. However, upon injury its expression is decreased in endothelial cells. While numerous FOXF1 downstream target genes have been identified, the upstream regulation of FOXF1 gene expression is poorly understood. Molecular mechanisms responsible for the FOXF1 transcript changes in injured lung endothelium remain unknown. In the first part of this dissertation, we employed immunostaining on injured mouse lung tissues, FACS-sorted lung endothelial cells from mice exposed to hypoxia and sequencing data from patients diagnosed with hypoxemic respiratory failure to demonstrate that hypoxia is associated with decreased FOXF1 expression. Our findings demonstrate that bleomycin-induced lung injury induced hypoxia in the mouse lung tissue which corresponded with decreased Foxf1 expression. Human FOXF1 mRNA was decreased in lungs of patients diagnosed with hypoxemic respiratory failure compared to lungs of patients that were not hypoxic. Mice exposed to hypoxia exhibited reduced Foxf1 expression in the lung tissue and FACS-sorted lung endothelial cells. In vitro, hypoxia (1% of O2) or treatment with cobalt (II) chloride increased HIF1-a protein levels but inhibited FOXF1 expression in three endothelial cell lines. Overexpression of HIF1-a in cultured endothelial cells was sufficient to inhibit FOXF1 mRNA. SiRNA-mediated depletion of HIF1-a prevented the downregulation of FOXF1 gene expression after hypoxia or cobalt (II) chloride treatment. Altogether, hypoxia inhibits FOXF1 expression in endothelial cells in a HIF1-a dependent manner. Our data suggests that endothelial cell-specific inhibition of HIF1-a via gene therapy can be considered to restore FOXF1 and improve lung repair in patients with severe lung injury. Additionally, while the role of FOXF1 in endothelial cells and fibroblasts within fibrotic lungs has been documented, its function in lung pericytes has not been elucidated. By employing a bleomycin-induced model of pulmonary fibrosis, we demonstrate a reduction in FOXF1 expression in lung pericytes. Preliminary findings outlined in the second part of the dissertation propose the potential involvement of FOXF1 in modulating pericyte activities in the context of fibrotic lung conditions.
Tanya Kalin, M.D. Ph.D. (Committee Chair)
Elisa Boscolo, Ph.D. (Committee Member)
Satish Madala, Ph.D. (Committee Member)
Marie-Dominique Filippi, Ph.D. (Committee Member)
Yanbo Fan, Ph.D. (Committee Member)
117 p.
Cellular Biology

Recommended Citations

Citations

  • Acharya, A. (2024). Regulation and Role of Forkhead Box F1 in lung injury [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1712911854126192

    APA Style (7th edition)

  • Acharya, Anusha. Regulation and Role of Forkhead Box F1 in lung injury. 2024. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1712911854126192.

    MLA Style (8th edition)

  • Acharya, Anusha. "Regulation and Role of Forkhead Box F1 in lung injury." Doctoral dissertation, University of Cincinnati, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1712911854126192

    Chicago Manual of Style (17th edition)

ucin1712911854126192
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© 2024, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.
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