# MALDI Imaging of Acute Organophosphate Exposure in KIKO Mice

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $479,989

## Abstract

Abstract
Three million people worldwide are exposed to organophosphates (OP), most of whom will survive with long
term side effects. These side effects include cognitive problems, mood disorders, and other neurological issues.
These side effects have underlaying molecular mechanisms which have yet to be uncovered. This knowledge
gap is a direct result of a lack of research tools available, however, two new tools have recently become available
to close this knowledge gap. The first is a novel mouse model, termed the KIKO mouse, which contains two key
genetic modifications: 1. knock out of the OP-binding serum carboxylesterase and 2. knock in of the human
acetylcholine esterase. These modifications produce a vastly improved rodent model of OP intoxication. The
other is matrix assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI). MALDI MSI
combines the power of mass spectrometry with spatial resolution. Briefly, discrete mass spectrometry
experiments are generated across a fresh-frozen tissue section to generate ion density maps of metabolites,
neurotransmitters, lipids, and N-glycans. These two novel and powerful tools will allow for unprecedented
molecular information on the short- and long-term effects of OP intoxication. We hypothesize that OP intoxication
generates significant molecular changes in neurotransmitters, metabolites, lipids, and N-glycans. Our preliminary
data shows significant differences in metabolites, neurotransmitters, and lipid oxidation in KIKO mice fifteen
minutes post-exposure. Literature data supports changes in N-glycans associated with neuroinflammation. To
test this hypothesis, in Aims 1 and 2, we will expose KIKO mice to 1xLD50 of sarin followed by the currently
fielded countermeasure 2-PAM and atropine. Control animals will be given an equivalent volume of water for
both exposure and treatment. Animals will be euthanized at 24 hours, 3-, 6-, and 12-weeks post exposure for
analysis of metabolites, neurotransmitters, lipids, and N-glycans from brain, spinal cord, and blood. In Aim 3 we
will expose pregnant KIKO mice to 1xLD50 of sarin followed by the currently fielded countermeasure. Dames will
be allowed to continue their pregnancy and the offspring will be euthanized at early adult (8 weeks), mature adult
(14 to 16 weeks), mid-life (40 weeks) and geriatric (78 weeks) of age for analysis by MALDI MSI. Brains, spines,
and blood will be collected for analysis of metabolites, neurotransmitters, lipids, and N-glycans. From these data
we will generate novel targets in the treatment of OP intoxication and its long term side effects.

## Key facts

- **NIH application ID:** 10851316
- **Project number:** 1R01NS136102-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Caitlin Tressler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $479,989
- **Award type:** 1
- **Project period:** 2024-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851316

## Citation

> US National Institutes of Health, RePORTER application 10851316, MALDI Imaging of Acute Organophosphate Exposure in KIKO Mice (1R01NS136102-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10851316. Licensed CC0.

---

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