# Hepatocyte Hippo Signaling Drives Inflammation in Liver Injury and Regeneration

> **NIH NIH R03** · YALE UNIVERSITY · 2021 · $125,625

## Abstract

Project Summary
The short-term goal of this proposal is to define how hepatocyte Yap signaling influences the recruitment and
characteristics of immune cell infiltration during liver injury and regeneration. Our long-term goal is to
understand the intimate cell-cell interactions that hepatocytes have with the tissue microenvironment to drive
liver fibrosis. Successful completion of this project would augment our ability to develop tailored medical
therapies for cirrhosis by focusing on particular arms of the Hippo Signaling pathway.
For several years, we studied the role that hepatocytes play in orchestrating regenerative responses, primarily
through the lens of Hippo Signaling, a potent growth regulatory pathway. In a prior proposal (K08DK105351),
we identified that by inducibly targeting hepatocytic Yap expression, this rapidly led to liver inflammation and
fibrosis. We predicted that in a similar fashion, chronic liver injury would increase hepatocytic Yap activity and
that this would directly lead to the development of liver inflammation/fibrosis. We have subsequently confirmed
the predictions of that study. In the process, we identified that inflammation is directly related to Yap levels in
hepatocytes and that Cyr61 is a key transcriptional target of Yap that is directly responsible for macrophage
cell recruitment and liver fibrosis.
This proposal seeks to extend these findings by using new tools to interrogate liver biology. In Aim 1, we will
characterize the origin, phenotype and contribution of the monocytes/macrophages that respond to
hepatocyte-specific Yap (Yap-Tg) activity in driving fibrosis. Using a combination of chemical and genetic
strategies to modify monocytes/macrophages activity we will define their contribution to inflammation/fibrosis in
the context of Yap-Tg. In Aim 2, we will interrogate the role of hepatocyte-derived Cyr61 in recruiting and
polarizing monocytes through in vivo overexpression and genetic knockout experiments. Mass cytometry and
high throughput RNA sequencing will be used to probe the immune landscape and changes in cellular
signaling in the context of Cyr61 loss and gain of function.
We propose that hepatocytes actively drive genetic programs after injury that remodel their local
microenvironment. Hepatocytic Yap activity plays a critical role in directing these programs with Cyr61 being a
particularly important downstream cytokine. Understanding the canonical and non-canonical mechanisms by
which Yap/Cyr61 recruit and polarize the immune cell environment will lead to improved models of
predicting the liver’s response to disease and facilitate directed treatment for cirrhosis.

## Key facts

- **NIH application ID:** 10259890
- **Project number:** 5R03DK124743-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** DEAN YIMLAMAI
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $125,625
- **Award type:** 5
- **Project period:** 2020-09-09 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10259890

## Citation

> US National Institutes of Health, RePORTER application 10259890, Hepatocyte Hippo Signaling Drives Inflammation in Liver Injury and Regeneration (5R03DK124743-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10259890. Licensed CC0.

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