NIH grant: Exploring embryonic exposure to hypoxia as a priming cue for postnatal epidermal insult (1F31AR087287-01)

retained text

NIH grant 1F31AR087287-01: Exploring embryonic exposure to hypoxia as a priming cue for postnatal epidermal insult
Institute: {'code': 'AR', 'abbreviation': 'NIAMS', 'name': 'National Institute of Arthritis and Musculoskeletal and Skin Diseases', 'admin_org_id': '12500006', 'admin_funding_url': ''}. PI: Charlotte Jeanne Bell. Award: $50114.
Start: 2026-08-01T00:00:00.
Project summary/abstract
 In barrier tissues, developmental transcription factors are often reactivated in cases of disease or
inflammation to drive expression of a suite of embryonic genes. While this reuse of pathways can prompt the
increased proliferation or migration characteristic of both states, other times the reason for repeated activity is
less clear. As an example, HIF1α activity during epidermal development within the hypoxic womb of most
mammals does not contribute to generation of proper skin structure, but reactivation after wounding is critical
for appropriate healing. One possible explanation for this bimodal activity is that the first wave of activation,
during development, might regulate the second wave. Prior work has demonstrated that epithelial stem cells are
capable of learning from their experiences, encoding epigenetic memories to respond to a stimulus more quickly
the second time encountered. These epigenetic memories are evident at the chromatin level as maintained
accessibility of stress-induced loci. If a similar phenomenon is active during development, it could serve to prime
epidermal stem cells to respond to inflammatory cues later in life.
 This hypothesis will be tested by modulating HIF1α activity during embryonic epidermal development
and carefully assessing resultant molecular changes. In utero lentiviral delivery of Cre to Hif1a fl/fl embryos will
selectively prevent epidermal Hif1a induction in the post-gastrulation embryo. Preliminary work supports that
HIF1α is dispensable for skin morphogenesis but drives substantial transcriptional changes in epidermal stem
cells. Notably, expression of hypoxia-induced target genes and chromatin-modifying enzymes is altered in the
absence of HIF1α. After further characterizing molecular changes, focusing on the chromatin landscape, next
experiments will leverage inducible systems to selectively perturb the first wave of HIF1α activity, leaving
postnatal activity intact. Inflammatory challenge of these animals will reveal whether embryonic HIF1α activity
has lifelong effects on stem cell function, as hypothesized. Moreover, bioinformatic analysis will uncover loci
throughout the adult genome which are poised in naïve homeostatic skin but are only expressed and essential in
HIF1α-activated situations such as wounding. When compared with epigenetic changes occurring in Hif1a-null
embryonic epidermis, I will learn if this poising occurs during embryogenesis and is reliant upon hypoxia. Hif1a
has not yet been implicated in epigenetic regulation of the skin, and exploring this function could have important
implications for wound healing and disease states of the skin where the protein is again stabilized.
 The proposed project will be conducted in the lab of Dr. Elaine Fuchs, PhD at the Rockefeller University.
The Fuchs lab provides a supportive environment with ample resources to explore the connections between
development and inflammation of the skin. Performing the above experiments will establish a robust foundation
in cellular and molecular biology techniques with skills in data analysis, critical thinking, leadership, mentorship,
and communication, providing strong support for a future independent scientific career in academia.

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