# Lung Endothelial Aß in infectious proteinopathy

> **NIH NIH R01** · UNIVERSITY OF SOUTH ALABAMA · 2023 · $385,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Pathogens responsible for nosocomial pneumonia elicit production of lung endothelial cell amyloids. These
amyloids can have antimicrobial properties and be beneficial to the host, or they can have cytotoxic properties
and be detrimental to the host. In the latter case, endothelial-derived amyloids may contribute to end organ
dysfunction in the aftermath of critical illness. Bacterial virulence factors, such as the Pseudomonas
aeruginosa type III secretion system effectors, and most notably exoenzyme Y, convert endothelial amyloids
from antimicrobial to cytotoxic species. Amyloid-beta (Aβ) is one of the cytotoxic amyloids generated following
endothelial infection. Aβ is released from endothelium where it becomes a transmissible and self-replicating
prion cytotoxin. Our preliminary data reveals that γ-secretase activating protein plays a critical role in
generating cytotoxic Aβ. We found γ-secretase activating protein expression in endothelial cells using non-
biased microarray, RNAseq, methylation and miRNA screens, and confirmed protein expression and function
in microvascular endothelium. γ-secretase activating protein deletion prevented formation of the cytotoxic Aβ
species. Rather, following γ-secretase activating protein deletion the Pseudomonas aeruginosa- and
exoenzyme Y-induced Aβ had antimicrobial properties. Exoenzyme Y is a promiscuous nucleotidyl cyclase that
results in protein kinase A activation, which may phosphorylate Aβ necessary to increase its cytotoxic activity.
These data suggest production of cytotoxic Aβ is due to two inter-related mechanisms, including an increase in
γ-secretase activating protein function and the phosphorylation of Aβ once it is produced. Hence, this proposal
tests the hypothesis that exoenzyme Y promotes the production of cytotoxic Aβ, dependent upon γ-secretase
activating protein.

## Key facts

- **NIH application ID:** 10650303
- **Project number:** 5R01HL148069-04
- **Recipient organization:** UNIVERSITY OF SOUTH ALABAMA
- **Principal Investigator:** Troy Stevens
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10650303

## Citation

> US National Institutes of Health, RePORTER application 10650303, Lung Endothelial Aß in infectious proteinopathy (5R01HL148069-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10650303. Licensed CC0.

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