# Intracranial pressure-mediated diffuse pathologies following traumatic brain injury

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $333,594

## Abstract

Project Summary
Traumatic brain injury (TBI) is a serious health care problem with staggering individual and societal costs.
Secondary elevation of intracranial pressure (ICP) is a major contributing factor in exacerbated TBI-initiated
morbidity in the human population. However, apart from the well-known relationship between high ICP and
hematoma/contusion expansion and/or ensuing global ischemia due to reduced CPP, virtually nothing
is known regarding the diffuse pathologies mediated by ICP. This lack of knowledge is highlighted by
the limited success of current therapies in overcoming the predisposition for negative outcomes
associated with elevated ICP post TBI. These issues have sparked intense debate over the clinical efficacy
of such ICP/CPP-based treatment strategies while also calling into question the current threshold of
20mmHg as a target for therapeutic intervention for elevated ICP post-TBI. Therefore, the long-term goal of
this study is to investigate ICP-mediated diffuse pathologies following TBI. Recently it was found that sub-
acute neuronal membrane poration is exacerbated in animals sustaining TBI and manually elevated ICP,
without attendant ischemia due to low CPP. Further there was suggestion that this pathology, extends for days
to weeks following injury, potentially via a cathepsin-B-mediated pathway, and is linked to ICP-mediated
chronic behavioral morbidity. In accordance with these findings the current project aims to 1) elucidate the
pathological progression of TBI-induced sub-acute cortical neuronal membrane poration and the
involvement of cathepsin-B-mediated molecular mechanisms in this pathology, 2) investigate the effect of
secondary ICP elevation on neuronal pathology and behavioral morbidity following diffuse TBI and 3)
determine if novel therapies targeting either inhibition of the cathepsin-B pathway or induction of
membrane resealing could alleviate exacerbated pathology and morbidity in the face of elevated ICP. These
aims will be addressed using a novel rat model of ICP elevation following diffuse TBI in concert with
fluorescent tracer infusion paradigms that allow for the identification and isolation of sub-acutely porated
neurons. This animal model will be paired with microscopic, molecular, and behavioral assessments to
evaluate ICP-mediated diffuse neuronal pathology and its link to morbidity following TBI. Together, these
studies are anticipated to greatly advance understanding of the pathologies modulated by secondary
elevations of ICP following TBI and could directly translate to enhanced clinical practice for the treatment
of elevated ICP in TBI patients.

## Key facts

- **NIH application ID:** 9828100
- **Project number:** 5R01NS096143-04
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Audrey D Lafrenaye
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $333,594
- **Award type:** 5
- **Project period:** 2016-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828100

## Citation

> US National Institutes of Health, RePORTER application 9828100, Intracranial pressure-mediated diffuse pathologies following traumatic brain injury (5R01NS096143-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828100. Licensed CC0.

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