# Response to Immune Associated Stress

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $478,931

## Abstract

PROJECT SUMMARY/ABSTRACT
Nrf1/2 (human) and SKN-1 (Caenorhabditis elegans ortholog) are key infection-related transcription factors
whose regulation is incompletely understood, representing a critical gap in knowledge. The long-term goal of this
research is to understand how the host alleviates stress during exposure to pathogens. The objective of this
application is to elucidate new mechanisms of SKN-1 regulation that contribute to its protective effects. The
central hypothesis is that NIPI-3 and CDC-48.1/2 are amongst previously unknown factors that positively regulate
SKN-1 to protect against immune associated stress. The rationale for this investigation is that the identification
of new regulators which control a conserved stress response under pathogenic conditions may allow for their
therapeutic modulation to alleviate infection induced pathology. The central hypothesis will be addressed by the
following aims. Specific Aim #1 will identify how NIPI-3 regulates SKN-1 activity. The working hypothesis,
based on preliminary and published data, is that NIPI-3 regulates SKN-1 activity in the intestine via CEBP-1.
Specifically, NIPI-3 is proposed to negatively regulate CEBP-1, to directly influence the amount and/or activity of
SKN-1 available to carry out its protective transcriptional response. Specific Aim #2 will elucidate the role of
CDC-48.1/2 in influencing SKN-1 activity. CDC-48.1/2 is hypothesized to elicit its effects on SKN-1 by its role
in the ER-associated degradation (ERAD) pathway. Specifically, it is proposed that CDC-48.1/2 shuttles SKN-
1A, the ER-tethered form of SKN-1, to the cytosolic side of the ER membrane, a process necessary for its
activation. However, CDC-48.1/2 is additionally predicted to ensure the proper trafficking of BLI-3, a NADPH
oxidase necessary for activating cytoplasmic SKN-1. Specific Aim #3 will identify additional factors that
regulate SKN-1 activity and pathogen resistance. In addition to CDC-48.1/2 and NIPI-3, other factors of in-
terest were found, including two that only affect SKN-1 activity on pathogen. In this aim, the screen will be com-
pleted and additional factors will be characterized. The approach is postulated to reveal further insights into the
mechanisms of SKN-1 regulation. Because SKN-1 and human Nrf orthologs protect against infection-related
stress, the research will have a significant impact on the understanding of the cytoprotective responses that
occur during the immune response. Knowledge of the targets and mechanisms that drive anti-inflammatory re-
sponses may allow for their eventual pharmacological targeting for the benefit of those suffering from damaging
immune responses. The proposed research is innovative because it identifies SKN-1 regulators under infectious
conditions, representing a substantive departure from previous studies.

## Key facts

- **NIH application ID:** 10769828
- **Project number:** 5R01AI150045-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Danielle A Garsin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $478,931
- **Award type:** 5
- **Project period:** 2020-03-13 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769828

## Citation

> US National Institutes of Health, RePORTER application 10769828, Response to Immune Associated Stress (5R01AI150045-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10769828. Licensed CC0.

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