# Sex differences in neurotrophin mediated neonatal neuroprotection: Role of ER alpha

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $339,883

## Abstract

Project Summary:
Hypoxia and ischemia (HI) related brain injury after perinatal asphyxia is a major cause of death and life-long
disability, occurring in 20,000 newborns every year in the United States. Female newborns are two times more
resistant to the effects of perinatal asphyxia, a phenomenon that is poorly understood. Our recent studies have
demonstrated a similar female bias in neuroprotection following neonatal HI in mice, and have clearly
implicated estrogen receptor alpha (ERa) in conferring this sex-specific neuroprotective mechanism. We
recently reported that ERa upregulation confers neuroprotection in the female neonatal hippocampus through
cross-talk with the neurotrophin receptor, tyrosine kinase B (TrkB), which has been shown to play an important
role in neuroprotection and improving long-term functional recovery in neonatal mice post-HI. Administration of
7,8-dihydroxyflavone (7,8-DHF; potent and selective TrkB agonist) increases TrkB phosphorylation and
hippocampal neuronal survival post-HI in female, but not in male newborn mice, and these female specific
effects are absent in the ERa null mutant mice. In preliminary experiments we have found that female-specific
upregulation of hippocampal ERa post-HI is dependent on a demethylating DNA repair factor, the growth
arrest and DNA damage-inducible protein 45 beta (Gadd45b). Additionally, when we treated females with
testosterone (T) during the perinatal period, subsequent HI-induced expression of hippocampal ERa is
reduced to male levels. In the proposed experiments, we will determine the mechanisms by which sex-specific
ERa expression and neuroprotection occurs following neonatal HI, and interrogate signaling pathways that
mediate ERa cross-talk with TrkB and thereby confer its neuroprotective effects. We will test the following aims
in mice and sexed hippocampal neurons following in vivo and in vitro ischemia, respectively: In Aim 1, we will
interrogate whether membrane ERa signaling mediates neuroprotection post-HI, and assess signaling
mechanisms that link ERa signaling to the membrane TrkB receptor. In Aim 2, we will interrogate if knockdown
Gadd45b alters the methylation status of the ERa gene promoter region in a female specific manner following
in vitro ischemia. In Aim 3, we will evaluate the effects of altered perinatal testosterone exposure on
ERa expression and the severity of long-term functional deficits. The work proposed in these aims will test the
novel hypothesis that sex-specific TrkB phosphorylation is mediated by HI induced ERa upregulation. An
improved understanding of the mechanisms underlying sex-based susceptibility to HI will provide new avenues
for future development of drug therapies for neonatal HI.

## Key facts

- **NIH application ID:** 10132420
- **Project number:** 5R01NS111021-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Pelin Cengiz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $339,883
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132420

## Citation

> US National Institutes of Health, RePORTER application 10132420, Sex differences in neurotrophin mediated neonatal neuroprotection: Role of ER alpha (5R01NS111021-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10132420. Licensed CC0.

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