# Treating AT Deficiency with Drugs that Modulate the Proteostasis Network

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2020 · $422,333

## Abstract

Project Summary
The classical form of α1antitrypsin deficiency (ATD) is one of the most common genetic causes of liver disease.
Liver transplantation represents the only treatment currently available. The liver disease associated with ATD
is characterized by a stereotypical chronic fibrosis leading to cirrhosis and hepatocyte hyper-proliferation that
predisposes to hepatocellular carcinoma. This pathology is attributed to the gain-of-function, proteotoxic effect
of mutant AT Z that accumulates in the endoplasmic reticulum (ER) of liver cells. My lab has elucidated the
potential mechanisms by which liver cells cope with the proteotoxic effects of ATZ accumulation in the ER
including a distinct set of intracellular degradation pathways (proteasomal and autophagic) and a distinct set of
signaling pathways that are specifically activated (autophagy, NFκB, ER- and mitochondrial-caspases but not
the unfolded protein response). Our working hypothesis is that pharmacological strategies which capitalize on
these naturally occurring, presumably protective proteostasis regulatory mechanisms will have a therapeutic
effect on the liver disease caused by ATD. Recently, we validated this hypothesis by showing that an
autophagy enhancer drug, carbamazepine (CBZ), promotes degradation of ATZ, reduces the hepatic ATZ load
and hepatic fibrosis in vivo in a mouse model. In the work proposed here we will pursue this hypothesis further
by investigating other drug candidates with putative actions specifically on the autophagy system, including
FDA-approved drugs, cyclodextrins and mucolipin agonists. The project will also capitalize on a C. elegans
ATD model-based high content screening platform (Proj 2) together with computational pharmacological
analyses (core B) to discover additional therapeutic candidates. Finally, we will investigate several sequence
variants that are candidate genetic modifiers arising from whole exome sequencing of a unique family and
cohort populations. These variants will be tested for validity in model systems (Proj 3, Cores A and C),
hopefully to move into diagnostic platforms and as novel targets for drug development that would enable state-
of-the art personalized medicine approaches.

## Key facts

- **NIH application ID:** 9994907
- **Project number:** 5P01DK096990-07
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** David H Perlmutter
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $422,333
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994907

## Citation

> US National Institutes of Health, RePORTER application 9994907, Treating AT Deficiency with Drugs that Modulate the Proteostasis Network (5P01DK096990-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9994907. Licensed CC0.

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