# Regulation of brain cholesterol homeostasis following neonatal hypoxia-ischemia

> **NIH NIH R56** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $520,165

## Abstract

Project summary/Abstract
Our long-term objectives are to define the complex mechanisms responsible for brain damage and repair
following neonatal hypoxia-ischemia (HI), as a model for neonatal encephalopathy (NE), and to search for
novel and specific diagnostic or therapeutic targets for HIE/NE.
In this proposal, we will investigate how neonatal HI impacts cholesterol homeostasis, which is crucial for brain
development due to its importance in membrane integrity, myelination, synaptogenesis and neurotransmission.
Our preliminary data shows that HI disturbs cholesterol homeostasis by inhibiting its synthesis and accelerating
its metabolism. We hypothesize that HI disturbs cholesterol biosynthesis; upregulation of CYP46A1, the brain-
specific hydroxylase responsible for cholesterol removal, contributes to HI brain injury; and the plasma level of
24S-HC, the enzymatic product of CYP46A1, can be used as a blood biomarker for evaluation of neonatal HI
brain damage. We will provide a comprehensive study of the changes in cholesterol synthesis following
neonatal HI (Aim 1) from the transcriptional level to the protein levels of the key enzymes; we will quantify the
cholesterol intermediates along its biosynthetic pathway using HPLC-MS & GC-MS. The contribution of
CYP46A1 to HI brain injury in vivo and in vitro (oxygen glucose deprivation) (Aim 2) will be determined by
manipulation of the CYP46A1 expression with lentiviral-mediated inducible CRISPR/cas9 knockout approach
in vitro and with specific CYP46A1 inhibitor in vivo. Finally, we will evaluate the value of plasma levels of 24S-
HC as a biomarker for neonatal HI brain injury (Aim 3). In a longitudinal study, we will determine the correlation
between blood 24S-HC with motor and cognitive impairments (behavioral tests) 6 weeks post-HI, with gray and
white matter injury evaluated by both MRI (T2W and DTI) and histological staining at 6 days and 6 weeks after
behavioral and MRI exams.
This proposal is designed to gain deep insights into the molecular regulation of brain cholesterol synthesis and
metabolism for a better understanding of lipid disorders, protein-lipid interactions and their implication in
neonatal HI. These important questions are largely unexplored in perinatal brain damage. These preclinical
data could help identify new and early-onset circulating biomarkers and potentially novel lipid-based
pharmacologic targets to ameliorate brain injury in HIE babies. Our studies have considerable translational
benefit to severely brain-damaged children.

## Key facts

- **NIH application ID:** 10201371
- **Project number:** 1R56NS114563-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Xiangning Jiang
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $520,165
- **Award type:** 1
- **Project period:** 2020-08-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201371

## Citation

> US National Institutes of Health, RePORTER application 10201371, Regulation of brain cholesterol homeostasis following neonatal hypoxia-ischemia (1R56NS114563-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10201371. Licensed CC0.

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