# Proteostasis Regulator Pharmacology Core D

> **NIH NIH P01** · NORTHWESTERN UNIVERSITY · 2021 · $321,809

## Abstract

The overarching aim of Core D, in collaboration with Projects 1-4 and cores B and C, is to test the hypothesis
that it is possible to partially reverse aging-dependent deficiencies in proteostasis network (PN) capacity
(including those leading to pathology) by pharmacologic regulation of the PN employing small molecule
proteostasis regulators. We will focus on heat shock response stress-responsive signaling pathway activators
that regulate cytosolic PN capacity, unfolded protein response stress-responsive signaling activators that
regulate secretory pathway PN capacity, and the antioxidant stress-responsive signaling pathway activators in
Aim 1. Since stress-responsive signaling pathways generate an active transcription factor, we hypothesize that
there will be a greater chance for an effective biological response from this evolved solution to correct
proteostasis deficiencies, wherein all the components of interacting and competing PN pathways in a given
subcellular compartment are up-regulated in the appropriate stoichiometry. These stress-responsive signaling
pathways lead to powerful emergent functions that are only partially understood. In Aim 1, we will further
develop a technology platform to validate the pharmacodynamics (PD; the study of what a drug does to the
organism), selectivity, and mechanism of action of small molecule proteostasis regulators that function through
activation of stress-responsive signaling pathways in multiple organisms. We will initially employ cell-based
reporters of stress-responsive signaling pathway activation (with Core B), targeted RNAseq, followed by mass
spectrometry-based proteomics (Core C activities), coupled to bioinformatics to validate the proteostasis
regulators. We will also assess the pharmacokinetics (PK; the study of what the organism does to a drug
(metabolism)) in multiple organisms, which will help us establish reasonable dosing regimens. PK will be
assessed using liquid chromatography-mass spectrometry approaches. In Aim 2, we also seek to establish the
utility of small molecule proteostasis regulators involved in enhancing the degradation of proteins, lipids and
organelles, either through activation of autophagy or the ubiquitin proteasome system. We will generate PK
and PD data for proteostasis regulators reported by others that activate the autophagy lysosomal pathway
(degrades proteins, oligosaccharides, lipids and oligonucleotides) through an m-TOR independent mechanism
and for proteostasis regulators to activate the ubiquitin proteasome system (degrades proteins). Collectively,
the PK and PD data in human, murine and yeast cells and in C. elegans is important because: (1) it allows us
to test and, therefore recommend, reasonable dosing regimens for proteostasis regulators, and (2) these data
allow us to properly interpret experiments in model organisms, especially negative data. We will provide these
validated proteostasis regulators to PIs of the projects, as well to labs working on c...

## Key facts

- **NIH application ID:** 10183113
- **Project number:** 5P01AG054407-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** JEFFERY W KELLY
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $321,809
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183113

## Citation

> US National Institutes of Health, RePORTER application 10183113, Proteostasis Regulator Pharmacology Core D (5P01AG054407-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10183113. Licensed CC0.

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