Thursday, April 3, 2025
4/3/2025
Activation of Nrf2 during embryonic development - mechanisms and consequences - Abstract Early life stage exposures to toxicants can result in islet malformations, which may predispose individuals to diabetes. The glutathione redox microenvironment plays fundamental roles in embryonic development and cell signaling, perturbation of which can result in functional or structural alterations that only become apparent with subsequent stress or age. Surprisingly little is known about how embryos respond to oxidative stress, or the impact of toxicant exposures on pancreatic β-cell development. This project takes a multi-level approach using state-of-the-art techniques to elucidate the complex pathophysiological mechanisms by which exposures to Per-and-polyfluoroalkyl substances (PFAS) that cause oxidative stress derail islet development, and the consequences for β-cell function. We test the central hypothesis that deviations from the GSH redox microenvironment and aberrant activation of the transcription factor Nrf2- at the wrong place and the wrong time- impair β-cell development and function. There are three overarching goals of this project: 1) to deepen our understanding of the role of Nrf2 activation in embryonic β-cells and islet development; 2) ascertain the impact of PFAS on insulin biosynthesis; and 3) identify β-cell fragility and bioindicators of later-life metabolic impacts that can be translated to human health. We will use transgenic zebrafish, confocal microscopy and immunofluorescence, redox proteomics and insulin misfolding assays, and cultured β-cells to investigate exposures to two common PFAS (PFOS, PFHxS), and a legacy aqueous film-forming foam (AFFF). This work will have a sustained and powerful impact on the fields of developmental toxicology, redox biology, and the developmental origins of health and disease and provides critical advances towards developing science-based PFAS guidelines, targets for clinical interventions, and public health policies.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).