# Deciphering Epithelial Signals in the Liver to Drive Inflammation and Fibrosis

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $418,824

## Abstract

Project Summary
The short-term goal of this proposal is to understand how Yap/Taz/Cyr61 signaling influences remodeling of
the liver parenchyma during acute and chronic injury. This proposal will functionally define the response of
non-parenchymal cells (NPCs) to changes in epithelial Yap/Taz/Cyr61 signaling and validate candidate
signaling pathways that lead to NPC activation and recruitment. Our long-term goal is to understand the
intimate interactions and cellular decisions made by liver cells to generate a well-compensated organ.
Successful completion of this project would augment our ability to tailor medical therapies for cirrhosis and its
sequela by focusing on particular arms of Yap/Taz/Cyr61 signaling.
For several years, we studied the role that Yap plays in orchestrating regenerative responses. While Yap (and,
its paralog Taz) have long-established roles in regulating cell proliferation, they are increasingly being
recognized as having important non-cell-autonomous roles in proper tissue regeneration. Yap and Taz share a
similar biochemical structure but are differentially expressed after injury. Our work as well as of others suggest
that Yap and Taz are differentially activated in liver injury and, likely have common and distinct biochemical
targets mediating their injury response. We propose to closely examine our models of Yap and Taz activity that
lead to fibrosis to dissect common and distinct mechanisms for each molecule. We will further refine our
understanding of Cyr61, a widely reported Yap/Taz target which has been reported to have both pro- and anti-
fibrotic roles.
In Aim 1, we will interrogate the cell-cell interactions after hepatocyte-specific activation of Yap (Yap-Tg) with
immune cells, liver sinusoidal endothelial cells, and fibroblasts using next-generation sequencing and
advanced imaging approaches. Chemical and genetic approaches interrogating potential drivers of the
phenotype will be used in the Yap-Tg model to examine its effects on hepatic stellate cell activation. In Aim 2,
we developed a hepatocyte-specific Taz overexpression model with distinctive characteristics from Yap-Tg.
This Taz model displays less inflammation, but a similar degree of fibrosis as the Yap-Tg model suggesting it
drives unique biochemical mechanisms. We will characterize the Taz fibrotic microenvironment of this model
and perform in-depth genomic and transcriptional profiling of Yap-Tg versus Taz overexpression. Aim 3 will
investigate potential mechanisms that Cyr61 can operate as a pro-fibrotic and anti-fibrotic molecule depending
on the injury setting.
We propose that a detailed understanding of epithelial Yap/Taz/Cyr61 signaling in liver injury, their cellular and
biochemical targets will inform the field regarding critical checkpoints to limit or reverse cirrhotic development.
PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

## Key facts

- **NIH application ID:** 10436378
- **Project number:** 5R01DK129552-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** DEAN YIMLAMAI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $418,824
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436378

## Citation

> US National Institutes of Health, RePORTER application 10436378, Deciphering Epithelial Signals in the Liver to Drive Inflammation and Fibrosis (5R01DK129552-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10436378. Licensed CC0.

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