# Impact of Heightened ER Stress on NLRP3 Activation in Aged Lung during Infection

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $423,750

## Abstract

Project Summary
With an aging population and pulmonary infections becoming an increasingly significant cause of morbidity and
mortality, there is an urgent need to investigate molecular pathways underlying these impairments and devise
new therapeutics that can stimulate innate immune responses within this population. Our results demonstrate
aged hosts have impaired inflammasome activation, decreased gene expression of several key components of
the NLRP3 signaling pathway, reduced caspase-1 activity, and diminished IL1β production in response to in
vitro and in vivo infection with S. pneumoniae. Using in vitro and in vivo aging murine models of S. pneumoniae
infection, we will employ cellular and molecular techniques to test our overall hypothesis that the NLRP3
inflammasome is necessary for protection against S. pneumoniae and age associated decreases in ER and
mitochondrial Ca2+ homeostasis results in impaired activation of the NLRP3 inflammasome in aged lung;
thereby, resulting in increased bacterial pathogenesis, tissue injury, and pneumonic edema in the elderly lung.
To test this hypothesis, we will examine the impact of heightened ER stress and the unfolded protein response
(UPR) on inflammasome activity (Aim 1) and the impact of aging on the maintenance of ER Ca2+ homeostasis
and subsequent modulation of inflammasome activity (Aim 2) in aged lung during S. pneumoniae infection.
Summary and impact: As pulmonary pneumococcal infections remain a substantial cause of morbidity and
mortality in the elderly, even in an era of routine adult vaccination, there is a pressing need to identify
mechanistic pathways that regulate innate immune responses and investigate novel therapeutics and
treatment strategies that reduce serious disease and improve clinical outcomes. Despite the identification of
factors that modulate the inflammasome, the impact of aging and age-enhanced levels of ER stress on the
regulation of NLRP3 responses, specifically in response to pathogenic stimuli, has not been extensively
studied. By establishing and dissecting a pivotal mechanistic link between ER stress regulation and
inflammasome signaling in aged lung during S. pneumoniae infection, this research proposal has high potential
to elucidate innovative regulatory pathways, expand current understanding of age associated changes in ER
homeostasis. Therapeutic strategies designed to target defects in innate signaling in the aged host will aid in
circumventing emergent strains of antibiotic resistant bacteria that continue to develop and may be utilized for
treatment against a wide variety of pathogenic stimuli. Completion of the aims proposed in this R01 will further
define the role of the NLRP3 inflammasome as an important innate signaling pathway during S. pneumoniae
infections as well as yield new therapeutics that can be readily tested in primary human cells and evaluated in
additional model systems.

## Key facts

- **NIH application ID:** 9967921
- **Project number:** 5R01AG052530-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Heather Winona Stout Delgado
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967921

## Citation

> US National Institutes of Health, RePORTER application 9967921, Impact of Heightened ER Stress on NLRP3 Activation in Aged Lung during Infection (5R01AG052530-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9967921. Licensed CC0.

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