# ER stress and neonatal hypoxia ischemia encephalopathy

> **NIH NIH R01** · LOMA LINDA UNIVERSITY · 2021 · $345,625

## Abstract

Neonatal hypoxia ischemia (HI) is an injury to the neonatal brain caused by interrupted blood flow. It occurs in
2-4 of 1000 full-term births and 60% of premature infants. It is the leading cause of mortality and morbidity
associated with life-long neurological impairments.
Endoplasmic reticulum (ER) stress is a major pathology encountered after HI, associated with dysregulation of
protein folding leading to apoptosis and inflammation. HI induced ER stress up regulates the pro-apoptotic
Inositol requiring enzyme-1 alpha (IRE1α) signaling pathway and is also associated with reactive oxygen species
(ROS) accumulation, mainly from the NADPH-dependent cytochrome P450 reductase (NPR) and P450 2E1
(CYP) complex.
Bax-inhibitor 1 (BI-1) protein, expressed on ER membrane, has been shown to play a major role in inhibiting ER
stress induced signaling pathways. BI-1 can directly bind to IRE1α thus inhibiting this pro-apoptotic pathway as
well as reduce ROS accumulation by dissociating the NPR-CYP complex.
The objective of this study is to establish BI-1s anti-apoptotic and anti-inflammatory effects in an in vitro oxygen
glucose deprivation (OGD) model and in an in vivo neonatal HI rat model as well as to elucidate the mechanisms
via which it confers its protective properties. Our central hypothesis is that (1) transfection of cells with Ad-
TMBIM6 vector will improve cell viability after OGD as well as help determine BI-s-1s major pathways; (2)
overexpression of the BI-1 protein in the brain, via Ad-TMBIM6 injection will improve recovery after neonatal HI
by reducing ER stress induced (a) neuronal apoptosis via inhibition of IRE1α signaling pathway and (b)
neuroinflammation via dissociation of the NPR-CYP complex and subsequent inhibition of ROS. Specific Aim 1:
To determine the role of ER stress signaling pathways in the anti-apoptotic and anti-inflammatory mechanisms
of BI-1 in an in vitro Oxygen Glucose Deprivation (OGD) model. Specific Aim 2: To determine whether BI-1
upregulation exerts its anti-apoptotic effects via the IRE1α signaling pathway in an in vivo neonatal HI rat model.
Specific Aim 3: To investigate the anti-inflammatory effects of BI-1 overexpression and the signalling pathways
involved in an in vivo neonatal HI rat model.
The long-term goals of this proposal are to: 1) establish BI-1 as main regulator of ER stress 2) establish BI-1s
signaling pathways after neonatal HI; 3) provide a basis for BI-1 as a potential therapeutic target.

## Key facts

- **NIH application ID:** 10059275
- **Project number:** 5R01NS104083-04
- **Recipient organization:** LOMA LINDA UNIVERSITY
- **Principal Investigator:** John H Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $345,625
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10059275

## Citation

> US National Institutes of Health, RePORTER application 10059275, ER stress and neonatal hypoxia ischemia encephalopathy (5R01NS104083-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10059275. Licensed CC0.

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