# Applying a Human Liver Microphysiology System to Develop Therapeutic Strategies for Non-Alcoholic Fatty Liver Disease (NAFLD)

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $662,067

## Abstract

We propose to apply four complementary technologies in a Quantitative Systems Pharmacology approach to
create a human experimental model of non-alcoholic fatty liver disease (NAFLD), the most rapidly growing
disease, and to use the model to test novel therapeutic strategies:1) Implement a vascularized, liver acinus
microphysiological system (vLAMPS) constructed with human patient-derived, liver cells, as an experimental
model to recapitulate early NAFLD phenotypes and as a platform to experimentally test novel therapeutics; 2)
Building on our experience in computational and systems biology, we will use RNAseq data from normal and
NAFLD patients to infer pathways of disease progression, to identify the potential molecular protein targets that
are in the inferred pathways, and to use our latent factor modeling approach and 3D similarity models to
identify drugs that statistically interact with the targets in these pathways; 3) We will employ our highly efficient
processes for generating mature iPSC-derived hepatocytes combined with gene editing to incorporate disease
engineered iPSC hepatocytes (conditional gain/loss of function) into the vLAMPS to begin testing patient
specific therapies; and 4) Apply phenotypic drug screening technologies.
NAFLD encompasses a spectrum of liver damage ranging from simple steatosis (NAFL) to more serious non-
alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Cirrhosis and HCC resulting
from progressive damage to the liver have become the third most common causes of liver transplants. The
disease pathogenesis of NAFLD is complex and confounded by the considerable inter-individual differences in
disease susceptibility, progression and complications, suggesting the need for a patient specific approach.
Studies have identified NAFLD associated gene signatures and single nucleotide polymorphisms (SNPs). In
particular, the SIRT1 gene that is downregulated in NAFLD, has been identified as a key regulator of
lipogenesis, gluconeogenesis, ER stress, fatty acid oxidation, urea cycle and the antioxidant response in
hepatocytes. A SNP in the patatin-like phospho-lipase domain-containing 3 (PNPLA3) gene is strongly
associated with hepatic steatosis, fibrosis, cirrhosis, and HCC. However, there continues to be major gaps in
our understanding of the pathogenesis of NAFLD. For example, despite its strong association with NAFLD, the
functional significance of the PNPLA3 variant is unknown. A major limitation in the elucidation of a mechanistic
role of PNPLA3 in NAFLD has been the interspecies differences in its expression and tissue-specific
distribution, suggesting the need for human cell models.
This combination of the technologies and approaches is expected to lead to new strategies for development of
repurposed and new therapeutics with the potential to slow or halt the progression of early NAFLD to the more
advanced, life threatening stages.

## Key facts

- **NIH application ID:** 10144833
- **Project number:** 5R01DK117881-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** D. Lansing Taylor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $662,067
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144833

## Citation

> US National Institutes of Health, RePORTER application 10144833, Applying a Human Liver Microphysiology System to Develop Therapeutic Strategies for Non-Alcoholic Fatty Liver Disease (NAFLD) (5R01DK117881-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10144833. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*