# Models of AT Deficiency Using Human Hepatocytes

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2021 · $615,644

## Abstract

SUMMARY
The proposed study aims to develop models of ATD using patient-derived cells and use these models to
confirm previously identified modifiers of ATD and test potential drug therapies for ATD in human cells. We
have shown that stem cell-derived hepatocyte-like cells (iHeps) generated by differentiating stem cells from
patients with liver vs. lung manifestations of ATD exhibit differences in ultrastructural morphology and kinetics
of mutant ATZ disposal. Based on these findings, we hypothesize that genetic variations other than the ATZ
mutation determine the clinical phenotype of ATD. As a part of the previous cycle of this program project, we
and our colleagues have used high throughput analysis in C. elegans using a siRNA library to identify several
genes that modify ATZ accumulation. The proposed project will reveal the differences in accumulation of ATZ
and its proteotoxicity in iHeps from various subsets of ATD patients delinieated by age of onset of liver
disease, disparate hepatic phenotype, presence of co-existing pulmonary disease or hepatocellular carcinoma,
and heterozygosity for the ATZ allele. We will also examine a) the extent to which in vitro characteristics of
iHeps correspond to various ATD clinical subsets, b) the role of genetic modulators on ATD liver disease
phenotypes, c) the response of iHeps to candidate drugs for the treatment of ATD, and d) whether the delay in
ATZ disposal that characterizes iHeps from ATD patients with severe liver disease is due to aggregation-prone
properties of ATZ. Finally, we will generate in vivo models of human ATD by repopulating the livers of
retrorsine-treated immune deficient rats with primary human hepatocytes and iHeps from ATD patients and
controls. The development of in vivo and in vitro models of ATD using patient-derived cells would greatly
benefit the discovery and validation of target genes for novel therapies of ATD and evaluation of potential
therapeutic drugs.

## Key facts

- **NIH application ID:** 10197889
- **Project number:** 5P01DK096990-08
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Ira J. Fox
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $615,644
- **Award type:** 5
- **Project period:** 2012-09-24 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197889

## Citation

> US National Institutes of Health, RePORTER application 10197889, Models of AT Deficiency Using Human Hepatocytes (5P01DK096990-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10197889. Licensed CC0.

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