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Deconvoluting Stress-Responsive Proteostasis Signaling Pathways for Pharmacologic Activation Using Targeted RNA
Julia M D Grandjean, Lars Plate, Richard I Morimoto1
1Department of Molecular Biosciences, Rice Institute for Biomedical Research , Northwestern University , Evanston , Illinois 60208 , United States.
ACS Chemical Biology
|March 2, 2019
Summary
Researchers developed a targeted RNA sequencing assay for cost-effective, medium-throughput screening of cellular stress responses. This method helps identify and validate compounds that activate heat shock (HSR) and oxidative stress (OSR) pathways, aiding drug discovery for proteostasis defects.
Area of Science:
- Cellular Biology
- Molecular Biology
- Pharmacology
Background:
- Cellular proteostasis is crucial for health, maintained by pathways like the heat shock response (HSR), oxidative stress response (OSR), and unfolded protein response (UPR).
- Dysregulation of proteostasis is linked to various diseases, making these pathways therapeutic targets.
- Current high-throughput screening (HTS) methods identify potential pathway activators but lack medium-throughput assays for potency and selectivity assessment.
Purpose of the Study:
- To develop a cost-effective, medium-throughput targeted RNA sequencing (RNAseq) assay for screening stress-responsive signaling pathway activation.
- To enable deconvolution of signaling pathways activated by chemical or pharmacologic agents.
- To assess the selectivity of compounds identified by HTS that target OSR and HSR.
Main Methods:
- Development and implementation of a targeted RNA sequencing (RNAseq) assay.
- Application of the assay to screen and deconvolve stress-responsive signaling pathways.
- Utilizing the assay to determine the selectivity of previously identified OSR and HSR activating compounds.
Main Results:
- The targeted RNAseq assay provides a cost-effective, medium-throughput method for assessing stress-responsive signaling.
- The assay successfully deconvolves signaling pathway activation by various agents.
- Compound selectivity for OSR and HSR pathways was effectively defined using this assay.
Conclusions:
- The developed targeted RNAseq assay is a valuable tool for medium-throughput screening of stress-responsive signaling pathways.
- This assay can be integrated into drug discovery programs aimed at developing pharmacologic activators of cellular stress responses.
- The assay facilitates the characterization of compound potency and selectivity, crucial for therapeutic development.
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