# Project 2: Protection of Blood-Brain Barrier Function

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $491,094

## Abstract

Project Summary – Project 2
Organophosphates (OPs) such as diisopropylfluorophosphate (DFP) are convulsant chemical threat agents that
can trigger seizures that progress to life-threatening status epilepticus (SE). The current standard of care (SOC)
for acute exposure focuses on the termination of SE but not necessarily on the protection against long-term
adverse neurological consequences often observed in survivors. Blood-brain barrier (BBB) dysfunction as a
consequence of acute OP intoxication has not been rigorously evaluated despite the possible relevance of BBB
integrity in preventing neurological pathologies that can arise following various brain insults including chemical
toxicosis. Moreover, the efficacy of therapeutic strategies that prevent or reverse BBB disruption to mitigate
spontaneous recurrent seizures (SRS) and cognitive dysfunction following OP-induced cholinergic crisis has not
been explored, even though there is a dire need to find new therapies that can address the limitations of the
current SOC. To tackle these major gaps, Project 2 will use a well-established rat model of DFP intoxication to
test the hypothesis that therapies that reverse BBB dysfunction when administered as adjuncts to SOC will
mitigate the long-term, adverse neurological consequences of OP intoxication. The scientific premise supporting
this hypothesis includes preliminary evidence demonstrating: (1) BBB leakage and the presence of
microhemorrhages in brains of rats acutely intoxicated with DFP as measured by gadolinium-contrast MRI; (2)
increased activity of known mediators of BBB disruption following acute DFP intoxication, consistent with the
hypothesis that TGFβ signaling could be involved in the long-term adverse neurological effects triggered by DFP
intoxication; and (3) blocking calpain proteolytic activity may prevent epileptogenesis. Our goals are to
characterize the spatiotemporal progression of BBB dysfunction following acute OP intoxication, identify the
mechanisms and engagement of therapeutic targets contributing to OP-induced BBB/neurovascular dysfunction
and determine the efficacy, safety and broad-spectrum activity of the therapeutic candidates (compound 10357
- promotes cell death of PAI-1-tPA+GFAP-astrocytes, IPW-5371 - TGFβ receptor 1 & 2 inhibitor, and MDL-28170
- calpain inhibitor). If successful, this Project could be a game-changer, since it will determine translational
biomarkers for identifying individuals at risk of developing chronic adverse neurological effects and identify
therapeutic candidates to improve long-term neurological outcome(s) when used as adjunctive therapy to SOC.
Moreover, given the similarities between the OP intoxication model and other general models of epilepsy, the
possible targets and/or therapies discovered could have broader application toward other epileptogenic injuries.
The exceptional integration of the experimental design, including the DFP model and the behavorial readouts,
across all three Proje...

## Key facts

- **NIH application ID:** 10684086
- **Project number:** 5U54NS127758-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** ANGIE GELLI
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $491,094
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10684086

## Citation

> US National Institutes of Health, RePORTER application 10684086, Project 2: Protection of Blood-Brain Barrier Function (5U54NS127758-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10684086. Licensed CC0.

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