# The Unfolded Protein Response and Neuroprotection in Stroke

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $347,813

## Abstract

Abstract
Ischemic stroke is a devastating medical condition for which no pharmacologic intervention is available, except
thrombolysis that can be used only for a small percentage of stroke patients. To improve stroke outcome, new
pharmacologic approaches must be considered, such as boosting endogenous pro-survival pathways. Here,
the unfolded protein response (UPR) is a promising target, because the UPR restores endoplasmic reticulum
(ER) function, which is critical for survival of stressed cells. The ER plays a pivotal role in folding and
processing newly synthesized proteins. ER function is impaired in a variety of stress conditions, including
stroke, which results in accumulation of unfolded/misfolded proteins in the ER, a condition called ER stress. To
resolve ER stress, the UPR activates adaptive responses that are mediated by 3 stress sensors in the ER
membrane – activating transcription factor-6 (ATF6), inositol-requiring enzyme-1 (IRE1), and protein kinase
RNA-like ER kinase (PERK). These UPR branches have 3 primary functions: 1) increase protein-folding
capacity, 2) decrease the ER load, and 3) eliminate accumulated unfolded/misfolded proteins from the ER. The
UPR also modulates other pro-survival pathways including O-linked β-N-acetylglucosamine (O-GlcNAc)
modification. Although we know that stroke impairs ER function and activates the UPR, we do not yet know
how the individual UPR branches define the fate and function of post-ischemic neurons in stroke, nor which
UPR branch or branches play a predominant role in stroke outcome. Such knowledge is essential to
developing a novel strategy to harness UPR pro-survival pathways for therapeutic benefits in stroke. Our long-
term goal is to develop strategies to boost UPR pro-survival pathways for therapeutic purposes in stroke. The
objective of this application is to establish the mechanistic link between the UPR and stroke outcome, and to
identify the UPR branch or branches that critically define recovery of neurologic function after stroke. Our
central hypothesis is that boosting pro-survival UPR and related pathways facilitates restoration of impaired ER
function and cellular homeostasis in post-ischemic neurons, thereby improving stroke outcome. Based on our
new unique UPR-selective and neuron-specific genetically modified mouse models, the hypothesis will be
tested in the following specific aims: 1) Determine the role of ATF6 activation in stroke outcome; 2) Determine
the contribution of the IRE1/XBP1/O-GlcNAc axis to stroke outcome; 3) Determine the role of the PERK branch
in post-ischemic protein synthesis and stroke outcome. The proposed research is significant because we
expect to uncover the mechanisms that link the UPR and downstream pathways to stroke outcome. Such
knowledge will be a pivotal platform for future studies aimed at establishing new and innovative approaches to
improve recovery of neurologic function after stroke, which critically defines quality of life for stroke pa...

## Key facts

- **NIH application ID:** 9930150
- **Project number:** 5R01NS099590-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Wei Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,813
- **Award type:** 5
- **Project period:** 2016-09-15 → 2021-12-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930150

## Citation

> US National Institutes of Health, RePORTER application 9930150, The Unfolded Protein Response and Neuroprotection in Stroke (5R01NS099590-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9930150. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*