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

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $41,993

## Abstract

PROJECT SUMMARY
 Within invertebrate and vertebrate model organisms, such as C. elegans and mice, evidence strongly
suggests 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 distinct
pathways of UPRER activation. These analyses will elucidate how a distal tissue can detect and respond to the
glial 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:** 9962273
- **Project number:** 5F31AG060660-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Melissa G Metcalf
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $41,993
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962273

## Citation

> US National Institutes of Health, RePORTER application 9962273, Cell Non-Autonomous Signaling of the Unfolded Protein Response of the ER by Glial Cells (5F31AG060660-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9962273. Licensed CC0.

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