# The physiological and genetic basis of gestational adaptations to hypoxia

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2024 · $425,095

## Abstract

Hypoxia is a common feature of gestational complications. Even when the origins of hypoxia vary (i.e.,
environmental hypoxia versus hypoxia limited to the placenta), there are shared, intermediate features in
placental physiology that are also common across mammals. These commonalities suggest that there are some
fundamental effects of hypoxia on placental development that negatively impact gestational outcomes. We
recently demonstrated that evolutionary adaptations to chronic hypoxia in high elevation environments protects
placental and fetal growth in deer mice act on mechanisms shared with humans. These results point to conserved
processes that are involved in both mediating the negative impacts of hypoxia on fetal outcomes and preventing
these effects. In this proposal, we address three key questions, the answers to which will significantly advance
our understanding of how placental responses to hypoxia contribute to adverse gestational outcomes
(particularly fetal growth restriction) and the genetic and cell type-specific mechanisms that underlie variation in
susceptibility to these complications. First, we ask how individual placental cell type responses hypoxia
contribute to tissue-level outcomes, including identifying the cell types that are responsible for tissue-wide
transcriptional signatures associated with fetal growth under hypoxia. To answer this first question, we generate
cell type-specific transcriptomes from placental tissues using single-nuclei RNAseq from highland-adapted and
non-adapted mice experimentally acclimated during gestation to hypoxia or normoxia. Second, we interrogate
the cis-regulatory variation that explains cell type-specific transcriptional variation by linking allele-specific gene
expression to chromatin conformation in placentas from F1 hybrid crosses of the aforementioned populations,
again in an experimental framework. Finally, our third aim asks how these cell type-specific hypoxia responses
contribute to organizational remodeling of the placental exchange structures by combining in vivo histological
approaches and in vitro experimental approaches focused on cell-autonomous function of a single, important
placental cell type. The proposed aims thus combine experimental approaches, cutting-edge sequencing
analyses, and molecular and cellular biology with the broader goal of resolving the genetic and developmental
processes by which natural genetic variation alters placental function and influences fetal outcomes. The results
of this research will advance our understanding of conserved physiology that shapes placental development and
pregnancy in mammals, thereby supporting broader research focused on gestational health and disease in
humans.

## Key facts

- **NIH application ID:** 10855693
- **Project number:** 1R01HD114615-01
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Kathryn Wilsterman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $425,095
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10855693

## Citation

> US National Institutes of Health, RePORTER application 10855693, The physiological and genetic basis of gestational adaptations to hypoxia (1R01HD114615-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10855693. Licensed CC0.

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