# Project III- Impact of Hypoxia-Ischemia and/or Inflammation on Lipid Rafts in Cerebellum

> **NIH NIH P01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $256,470

## Abstract

In the term newborn (equivalent to the postnatal day (PN) 10 rat), the cerebellum is vulnerable to the effects of
hypoxia-ischemia. During this period of time, rapid change in the cerebellum is taking place: the cerebellar
Purkinje neurons, the deep cerebellar nuclear neurons and the cerebellar granule cells are rapidly proliferating,
and extending their axons and the numbers of cerebellar microglia are increasing. Our lab is focused on lipid
raft function and dysfunction in the cerebellum and in other neurodevelopmental disorders with a primary focus
on ethanol, the causative agent of fetal alcohol spectrum disorder. Lipid rafts are dynamic microdomains of the
plasma membrane which regulate signal transduction and protein trafficking. Hypoxia/ischemia (H/I) may
cause alterations in signaling or generate reactive oxygen species (ROS). ROS may cause oxidation of lipids
and therefore lipid raft dysfunction. These changes can lead to altered cerebellar development with long term
consequences for cerebellar function. L1 cell adhesion molecule (L1), a molecule critical for brain
development, and the toll like receptor, TLR4, can be used as reporters for lipid raft function in cerebellar
granule neurons (CGN), Purkinje neurons (PN), deep cerebellar nuclear neurons (DCN) and cerebellar
microglia. Choline, an essential nutrient and precursor to phosphatidylcholine (PtdCho) and sphingomyelin
(SM), both important in lipid raft regulation, improves lipid raft function and behavior following alcohol
exposure. Our preliminary data using PN7 rats shows that lipid rafts are dysfunctional in the cortex following
H/I and that choline/GM1 ganglioside partially prevents this effect. In addition, choline supplementation
protects L1 signaling, lipid raft distribution and cerebellar mediated behavior from the effects of other
neurotoxicants. Our hypothesis is that H/I at PN10 causes lipid raft dysfunction in CGN, PN, DCN and
microglia leading to poor cerebellar function. Inflammation caused by LPS synergistically increases this
dysfunction, and hypothermia, choline, and/or ceftriaxone will partially ameliorate these effects. We will use
PN10 rat pups (term equivalent) and the modified Rice-Vanucci model of H/I. Our three specific aims are: 1)
Determine lipid raft function and composition in whole cerebellum and CGN, PN and DCN following H/I with or
without prior LPS induced inflammation; 2) Determine lipid raft function and composition in cerebellar microglia
following H/I with or without prior LPS induced inflammation; 3) Determine if hypothermia, choline, and/or
ceftriaxone ameliorates 1) the acute alterations in function and composition of lipid rafts after H/I and H/I with
prior inflammation in cerebellum, CGN, PN, DCN and microglia; 2) effects of H/I with or without inflammation
on cerebellar related behaviors. Our overarching goal is to reduce the morbidity associated with H/I in
neonates.

## Key facts

- **NIH application ID:** 9979924
- **Project number:** 5P01HD085928-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** CYNTHIA FRANCES BEARER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $256,470
- **Award type:** 5
- **Project period:** 2016-08-17 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979924

## Citation

> US National Institutes of Health, RePORTER application 9979924, Project III- Impact of Hypoxia-Ischemia and/or Inflammation on Lipid Rafts in Cerebellum (5P01HD085928-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979924. Licensed CC0.

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