# Placental identified NHIP regulating neuronal oxidative stress in autism

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $670,005

## Abstract

The human fetal brain consumes up to 60% of the body’s oxygen and energy consumption,
despite making up ~13% of body mass. When the demand for oxygen in the placenta and
developing brain exceeds its supply, hypoxia is induced, followed by changes to mitochondrial
respiration, protein translation, and oxidative stress. Oxidative stress and epigenetic mechanisms
within the placental-brain axis act at the interface of genetic and environmental risk factors in
autism spectrum disorders. Using placental samples from a prospective high-risk cohort, we
recently identified and named a novel gene NHIP (neuronal hypoxia inducible, placenta
associated) and demonstrated its epigenetic, genetic, and transcriptional association with autism.
NHIP is transiently expressed in response to hypoxia and neuronal differentiation, two examples
of elevated oxidative stress. NHIP encodes a previously undiscovered micropeptide that localizes
to the nucleus and is predicted to be neuroprotective, based on the lower expression of NHIP in
placenta and brain samples from autism compared to control. The predicted structure of the NHIP
peptide is an amphipathic helix that has similarity to a 9aaTAD motif found in transcriptional
activation domains of many DNA binding proteins. We propose to test the hypothesis that NHIP
acts as a competitive inhibitor of multi-protein complexes, thereby protecting developing and
differentiating neurons following transient waves of hypoxia. Because NHIP is an “undiscovered
protein” whose function had not been described before our recent study, this proposal will focus
on the major research questions that are critical for determining the therapeutic relevance of
NHIP. Specifically, what is the function of NHIP in neurons and brain, how is it regulated in
response to hypoxia, and is it protective of neuronal oxidative stress? We propose three specific
aims using well-characterized in vitro and in vivo models, including an inducible human neuronal
cell line (LUHMES) engineered for NHIP transcript or peptide loss, human brain extracts with
known NHIP genotype and expression levels, and mouse brain following NHIP peptide
administration and/or hypoxia. Aim 1 will determine the molecular mechanisms of NHIP function
and examine both protein-specific and global cellular impacts of NHIP loss. Aim 2 will determine
how NHIP is transcriptionally responsive to hypoxia-induced oxidative stress by identifying the
transcription factors and their genetic and epigenetic requirements for binding to the NHIP
promoter and enhancer. Aim 3 will determine if exogenously delivered NHIP/NHIP protects
neurons and embryonic neural precursor cells from hypoxia-induced oxidative stress. Together,
the results from these proposed studies will provide the first functional characterization of NHIP,
an understudied micropeptide that is associated with resilience to autism spectrum disorders. The
potential impact of these results will be a potential therapeutic small molecule that ...

## Key facts

- **NIH application ID:** 10907835
- **Project number:** 5R01HD112991-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Janine M LaSalle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $670,005
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907835

## Citation

> US National Institutes of Health, RePORTER application 10907835, Placental identified NHIP regulating neuronal oxidative stress in autism (5R01HD112991-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10907835. Licensed CC0.

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