# Adapting Secretory Proteostasis through Pharmacologic IRE1 Activation

> **NIH NIH F31** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $21,970

## Abstract

Imbalances in protein homeostasis (or proteostasis) are implicated in the onset and pathogenesis of etiologically-
diverse diseases including diabetes, systemic amyloid disease, heart disease, and aging-related 
neurodegenerative disorders such as Alzheimer’s Disease (AD). There are currently no treatments for these 
diseases, prompting an effort to both understand disease pathogenesis and develop novel approaches to 
mitigate the associated pathogenic proteostasis imbalances. As the overall integrity of the cellular proteome is a 
central facet of viability and function, the cell evolved a proteostasis network comprised of folding and 
degradation factors to ensure proper folding of nascent or misfolded peptides, or to promote their degradation if 
folding cannot be achieved. The endoplasmic reticulum (ER) Unfolded Protein Response (UPR) plays a crucial 
role in maintaining both intra- and extra-cellular proteostasis, as the ER environment is a main checkpoint for 
the folding of secreted proteins. Importantly, many proteins implicated in proteostasis-associated diseases 
including AD are trafficked through the secretory pathway and therefore interface with the ER proteostasis 
environment. Thus, the UPR is an attractive target for manipulating the levels of destabilized, disease-relevant 
proteins. This response is normally activated under circumstances of increased misfolded protein load in the ER 
lumen (i.e., ER stress), a signal which is sensed and transduced by the ER membrane proteins Inositol Requiring 
Enzyme 1 (IRE1), Protein kinase-like Endoplasmic Reticulum Kinase (PERK), and Activating Transcription 
Factor 6 (ATF6), which in turn induce proteostatic transcriptional programs to mitigate the unfolded protein load. 
This research project focuses specifically on the IRE1 signaling arm of the UPR, which has been extensively 
studied using genetic and chemical genetic approaches to demonstrate the therapeutic potential for activation 
of this pathway for multiple, etiologically-diverse diseases. While these approaches have been transformative 
for studying IRE1 signaling, compounds currently available for pharmacologic activation of this pathway are 
limited by their inherent promiscuity and cellular toxicity. For this research project, I utilize a luciferase-based 
high-throughput screening approach in conjunction with transcriptomic and proteomic studies to identify novel 
small molecule activators of the IRE1 signaling axis with a defined mechanism of action (Aim 1). Through these 
efforts, I have prioritized compound 474 as a promising first-in-class, non-toxic and specific activator of the IRE1 
signaling axis in multiple cell culture models. In an effort to characterize the therapeutic potential of 
pharmacologic IRE1 activation, I will apply this compound and others to cellular models of AD to study effects 
on destabilized Amyloid Precursor Protein (APP) and Amyloid beta (Abβ) peptide levels as well as downstream 
physiological r...

## Key facts

- **NIH application ID:** 9939276
- **Project number:** 5F31AG063489-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Julia Marie Dendle Grandjean
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $21,970
- **Award type:** 5
- **Project period:** 2019-04-26 → 2020-11-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939276

## Citation

> US National Institutes of Health, RePORTER application 9939276, Adapting Secretory Proteostasis through Pharmacologic IRE1 Activation (5F31AG063489-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9939276. Licensed CC0.

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