# Investigating how intestinal innate immunity confers neuroprotection using C. elegans

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $332,768

## Abstract

Mitochondrial homeostasis is required to maintain neuronal health and function, and its
dysregulation plays prominent roles in rendering specific neural systems vulnerable. Recently
we have found that the activation of the p38 mitogen-activated protein kinase (MAPK; the
mammalian p38α ortholog) and the CREB like transcription factor ATF-7-mediated innate
immune pathway in the intestine of C. elegans can protect its neurons from degeneration
induced by mitochondrial dysfunction. The neuroprotective effects of p38MAPK/ATF-7
immunity activated in the gut occurs through the enhancement of mitophagy, and
p38MAPK/ATF-7 activity in intestinal cells alone is sufficient to lower mitochondrial numbers,
not only in intestinal cells, but also in neurons. Moreover, preliminary data obtained in our lab
show that in C. elegans the peripheral increase in disease-related misfolded proteins can
disrupt innate immune signaling pathways. Our central hypothesis, therefore, is that
aging- and proteotoxicity-induced dysregulation of the immune system can disrupt
mitochondrial homeostasis in neurons initiating or aggravating neurodegeneration.
The objective of the proposed research is to determine how the p38MAPK/ATF-7-mediated
innate immune pathway activated in the gut in C. elegans affects mitochondrial homeostasis
in neurons. To do this, we will:
Aim 1: Examine the role of the innate immune response in the maintenance of neurons
upon Complex I dysfunction.
Aim 2: Identify the immune mediators in the gut that affect neuronal health.
Aim 3: Examine the role of peripheral proteotoxic antigens in disrupting immune signaling,
leading to the accumulation of dysfunctional neuronal mitochondria.
Our preliminary data show that the innate immune response modulates mitochondrial
homeostasis in a cell non-autonomous manner, and is in turn can be inhibited by specific
peripheral proteotoxic antigens. These studies therefore offer the novel possibility that
immunosenescence is responsible for the accumulation of dysfunctional mitochondria, and
could offer new insights into the role of proteotoxicity in the modulation of mitochondrial
homeostasis.

## Key facts

- **NIH application ID:** 9926205
- **Project number:** 5R01AG060616-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Veena Prahlad
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $332,768
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926205

## Citation

> US National Institutes of Health, RePORTER application 9926205, Investigating how intestinal innate immunity confers neuroprotection using C. elegans (5R01AG060616-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9926205. Licensed CC0.

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