# Cell Non-Autonomous Signaling of the Unfolded Protein Response of the ER by Glial Cells

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA BERKELEY · 2021 · $37,509

## Abstract

PROJECT SUMMARY
No Changes to Parent Grant
Within invertebrate and vertebrate model organisms, such as C. elegans and mice, evidence stronglysuggests
that tissue-specific manipulations of stress response pathways can signal systemically and induce these
pathways in distal tissues. Compartmental proteotoxic stress in one tissue can be communicated to distal
tissues and induce genetic pathways of the endoplasmic reticulum unfolded protein response (UPRER).We have
shown that both neuronal and glial overexpression of the UPRER transcription factor, XBP-1s, in C. elegans
causes upregulation of the stress responsive UPRER in unconnected, peripheral tissue. While originating from a
single tissue, these manipulations appear capable of propagating synchronous changes to age-related and
stress resistance phenotypes across multiple tissues and organs. This cell non-autonomous response
reinforces the idea that in a multi-cellular organism, the sensing of protein stress can be conveyed and
responded systemically across the organism. However, the genetic requirements necessary for this signaling
mechanism remain unknown.
We hypothesize that glial XBP-1s induces a trans-tissue signaling mechanism to coordinate an organism-wide
stress response, longer lifespan, and improved metabolic state. This grant proposal seeks to identify the
genetic requirements for both signaling and sensing glial activation of the cell non-autonomous UPRER. From
an unbiased mutagenesis screen used in Aim 1, we will identify potential mediators of the cell non-autonomous
induction of the UPRER that will provide potential therapeutic targets for aging and metabolic disorders.
Additionally, in Aim 2 we propose to characterize both cell-autonomous and cell non-autonomous activation of
the UPRER to determine differences in the proteome and transcriptome of these seemingly distinctpathways of
UPRER activation. These analyses will elucidate how a distal tissue can detect and respond to theglial signal
deriving from UPRER activation, and potentially discover novel cellular signals or aberrations sensed by the
UPRER machinery.
This proposal addresses a gap in the field of cellular stress response by dissecting how these pathways are
systemically activated and communicated. Additionally, this research will advance the emerging field of glial
biology through exploration of the enigmatic molecular mechanisms and functional consequences of glial
signaling. Moving forward, this research will provide a basis for further investigation into the genetic pathways
of cell non-autonomous signaling that increase longevity and stress resistance in mammals. Answering the
questions described in this proposal will have therapeutic implications not only for normal aging, but also age-
onset diseases.

## Key facts

- **NIH application ID:** 10398380
- **Project number:** 3F31AG060660-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Melissa G Metcalf
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $37,509
- **Award type:** 3
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10398380

## Citation

> US National Institutes of Health, RePORTER application 10398380, Cell Non-Autonomous Signaling of the Unfolded Protein Response of the ER by Glial Cells (3F31AG060660-03S1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10398380. Licensed CC0.

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