# Adenosine deaminase 2 regulates macrophage phenotype and liver fibrosis in nonalcoholic fatty liver disease

> **NIH NIH K08** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $167,400

## Abstract

PROJECT SUMMARY/ABSTRACT
Dr. Zhenghui Gordon Jiang, a physician in Gastroenterology at Beth Israel Deaconess Medical Center (BIDMC)
and an Instructor in Medicine at Harvard Medical School, has a career goal to establish himself as an
independent physician-scientist in the field of nonalcoholic fatty liver disease (NAFLD), steatohepatitis (NASH),
and liver fibrosis. In addition to running a NAFLD specialty clinic, Dr. Jiang currently spends 70% of his time in
translational research supported by the Department of Medicine at BIDMC and external funding such as the
CTRA award from the Liver Research Foundation. A K08 award will further provide the protected time and
support necessary for him to accomplish the following goals in NAFLD research: 1) define the mechanism by
which adenosine deaminase 2 (ADA2) modulates macrophage (MØ) phenotype; 2) establish the impact of ADA2
on inflammation and fibrosis, and 3) test the associations of circulating ADA2 activity with insulin resistance,
inflammation and liver fibrosis in NAFLD. Drs. Simon Robson and Kenneth Mukamal are complementary
mentors on mechanistic and translational aspects of this project. Dr. Jiang has also identified a panel of advisors
and assembled a group of collaborators. Drs. Barbara Wegiel and Yury Popov at BIDMC will provide guidance
on MØ and fibrosis research respectively. Dr. Majken Jensen at Harvard Chan School of Public Health will advise
on the use of large clinical database and stored samples from the Multi-Ethnic Study of Atherosclerosis (MESA).
A proportion of NAFLD patients will develop inflammation and progressive fibrosis ultimately leading to cirrhosis
and liver cancer. The mechanism behind this difference in the natural history of NAFLD patients is unclear.
Recent work has suggested that the activity of ADA2 in the blood, an ecto-enzyme that catalyzes the conversion
of adenosine to inosine, correlate with the histological stage of liver fibrosis in NAFLD patients. Furthermore, MØ
in the portal area express ADA2 and accumulate in the setting of steatohepatitis and fibrosis. Our preliminary
studies point to the involvement of a novel ADA2 and adenosinergic pathway in regulating inflammation and
fibrosis in NAFLD. The central hypothesis is that ADA2 modulates MØ phenotype and influences liver fibrosis
in NAFLD. Dr. Jiang further postulates that ADA2 released by infiltrative MØ activates other immune cells in the
liver, including Kupffer cells, and perpetuates liver fibrosis and hepatic insulin resistance. The hypothesis will be
tested by pursuing two specific aims: Aim 1. To define the ADA2 pathway in modulating MØ by elucidating the
immune phenotype associated with ADA2 production, and the mechanism and impact of ADA2 action in vitro
and in NAFLD. Aim 2. To define the relationship of circulating ADA2 activity with inflammation, insulin resistance
and liver fibrosis among individuals with NAFLD in the Multi-Ethnic Study of Atherosclerosis.
The proposed studies will build upon ...

## Key facts

- **NIH application ID:** 9982962
- **Project number:** 5K08DK115883-03
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Zhenghui Gordon Jiang
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $167,400
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982962

## Citation

> US National Institutes of Health, RePORTER application 9982962, Adenosine deaminase 2 regulates macrophage phenotype and liver fibrosis in nonalcoholic fatty liver disease (5K08DK115883-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9982962. Licensed CC0.

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