# Effects of Perinatal Hypoxia-Ischemia on the Developing Cerebellum With and Without Prior Inflammation

> **NIH NIH P01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $1,266,809

## Abstract

Overall Project Summary
Neonatal hypoxia-ischemia (H/I) remains a major health issue with limited therapeutic approaches. The life
long consequences to both infant and caregivers demands we increase our knowledge regarding the origins,
consequences and prevention of brain damage around the time of birth. Clinical evidence increasingly points
to the cerebellum as a region that is profoundly but more diffusely impacted by neonatal H/I and this damage
reverberates as additional damage ensues to the regions with which it shares reciprocal connections. Yet the
cerebellum has been largely ignored in preclinical models of neonatal H/I. This proposal models H/I in the term
human infant, a time of heightened sensitivity for the cerebellum. Insults that occur during narrow sensitive
periods can have enduring effects by derailing dynamic developmental processes that can never be reset.
Often neonatal H/I is compounded by earlier, and perhaps undetected, neuroinflammation. Thus we propose to
conduct an in-depth first-of-its-kind analysis of the developing cerebellum after neonatal H/I with and without
prior inflammation. We attack the question with three Specific Aims. SA1: Develop an animal model of term H/I
with and without prior inflammation that has construct validity for clinical evidence of cerebellar damage in
newborns. SA2: Integrate neuroanatomical, metabolic, signal transduction and behavioral endpoints relevant to
cerebellar damage in this animal model. SA3: Test the neuroprotective effects of agents that inhibit
neuroinflammation, restore metabolism and/or prevent dysregulated signal transduction and thereby create a
preclinical foundation for translation in the immediate future. These aims will be achieved via four independent
projects and synergy assured by provision of animals, histology and behavioral testing from the Animal and
Behavioral Core (Core B). Each project is headed by an expert PI. Project I (McCarthy) - microglia as the
brain's innate immune system and their role in normal cerebellar development and impact on damage, Project
II (McKenna) - metabolism and its response to and role in damage, and Project III (Bearer) - lipid rafts as
essential signaling elements disrupted by H/I and inflammation. Project IV (Waddell), an R03 pilot project,
explores the novel use of eye blink conditioning, a well known cerebellar controlled learning paradigm, to
assess the cognitive impact of neonatal H/I. Microglia both respond to and produce inflammation which can, if
not arrested, become a run away and enduring pathological response. Metabolism and energy use is an
important determinant of damage following H/I, with high energy areas at greater risk, including the cerebellum.
Use of MALDI-MSI imaging will provide detailed high resolution relevant to lipids, neurotransmitters, oxidative
stress and metabolism. Lipid rafts are critical components of neural development yet they have been largely
unexplored in the context of H/I. All experiments includ...

## Key facts

- **NIH application ID:** 9979910
- **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:** $1,266,809
- **Award type:** 5
- **Project period:** 2016-08-17 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979910

## Citation

> US National Institutes of Health, RePORTER application 9979910, Effects of Perinatal Hypoxia-Ischemia on the Developing Cerebellum With and Without Prior Inflammation (5P01HD085928-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979910. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*