Jennifer Chen, MD

Assistant Adjunct Professor
M_MED-ZSFG-GAST
Research Description: 

Hepatic fibrogenesis is the molecular process that leads to end-stage liver disease, and there are currently no FDA-approved therapies that target this process. During my clinical training in internal medicine and hepatology, I was struck by the lack of therapies available for my patients with chronic liver disease and by how the vast majority were unaware of their diagnosis of hepatic fibrosis. As a physician-scientist trained in hepatology, my research program is focused on developing a precision approach for the diagnosis and treatment of hepatic fibrogenesis to improve the care of my patients with chronic liver disease.

We previously performed a small molecule screen to identify mechanisms that inactivate hepatic stellate cells (HSCs), the primary cell type responsible for hepatic fibrosis. We identified several targets, including the enzyme acid ceramidase (aCDase). Our studies uncovered a novel signaling network through which aCDase inhibition regulates phosphorylation and degradation of YAP/TAZ, key effectors of the Hippo signaling pathway. We validated aCDase as an antifibrotic target using conditional genetic knockout and pharmacologic approaches, and demonstrated that targeting aCDase inhibits YAP/TAZ activity, decreases matrix stiffness, and reduces fibrosis development and promotes fibrosis regression using multiple mouse models of fibrosis. Our data also show that aCDase inhibition reduces fibrogenesis in fibrotic rat and human liver tissues ex vivo. We also developed a gene signature score, the ceramide responsiveness score, which is significantly increased in NASH patients with advanced fibrosis.

Current projects in our research laboratory include identification of the upstream and downstream targets of the acid ceramidase-YAP/TAZ pathway; the development of novel aCDase inhibitors in partnership with medicinal chemists William DeGrado and Hyunil Jo for the treatment of hepatic fibrosis and hepatocellular carcinoma; and the refinement and validation of gene signature scores as biomarkers for hepatic fibrogenesis. We are also pursuing additional novel antifibrotic targets.

Primary Thematic Area: 
Tissue / Organ Biology & Endocrinology
Secondary Thematic Area: 
Cancer Biology & Cell Signaling
Research Summary: 
Dr. Jennifer Y. Chen’s research program focuses on the development of novel antifibrotic therapies and biomarkers for patients with chronic liver disease.

Websites

Featured Publications: 

Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells.

Scientific reports

Chen JY, Newcomb B, Zhou C, Pondick JV, Ghoshal S, York SR, Motola DL, Coant N, Yi JK, Mao C, Tanabe KK, Bronova I, Berdyshev EV, Fuchs BC, Hannun Y, Chung RT, Mullen AC

Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins.

Genome medicine

Zhou C, York SR, Chen JY, Pondick JV, Motola DL, Chung RT, Mullen AC

Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice.

Science translational medicine

Alsamman S, Christenson SA, Yu A, Ayad NME, Mooring MS, Segal JM, Hu JK, Schaub JR, Ho SS, Rao V, Marlow MM, Turner SM, Sedki M, Pantano L, Ghoshal S, Ferreira DDS, Ma HY, Duwaerts CC, Espanol-Suner R, Wei L, Newcomb B, Mileva I, Canals D, Hannun YA, Chung RT, Mattis AN, Fuchs BC, Tager AM, Yimlamai D, Weaver VM, Mullen AC, Sheppard D, Chen JY