Dissecting the molecular and cellular mechanisms of Alagille Syndrome

Funding Type: 
Basic Biology IV
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Alagille syndrome (ALGS) is caused by mutations in the so-called Notch pathway. The defects seen in ALGS patients, including abnormal bile ducts in the liver, and the known role of Notch in stem cells suggest that ALGS arises from defective interactions between different cell types, including liver progenitors, during development. However, this idea has not been directly tested, in part because of the inherent difficulty of studying human development.

A major recent scientific advance has been the possibility to generate and culture induced pluripotent stem cells (iPS cells). iPS cells can propagate indefinitely in culture and be induced to generate all the mature cell types in the body, including liver cells. Compared to embryonic stem cells, which comes from early embryos, iPS cells are generated from a small number of any mature cell type by expression of reprogramming factors.

We propose here to generate iPS cells from ALGS patients, starting from small numbers of skin cells from these patients. We will use these cells to investigate the molecular and cellular basis of the liver defects observed in ALGS. These experiments include the development of assays to recapitulate human liver development in culture. We hope that these experiments will allow us to better understand the basis of ALGS and the role of Notch in stem cells. A better understanding of liver development may also help identify novel regenerative strategies for patients with a wide range of liver diseases.

Statement of Benefit to California: 

Alagille syndrome (ALGS) is a rare disease (1 in ~70,000 births – less than 10 new cases in California every year) but the signaling pathway that is mutated in ALGS patients, the Notch pathway, is important for many developmental processes and its alteration contributes to the development of many diseases, including cancer, hereditary stroke, and multiple sclerosis.

In addition, liver disease affects a wide range of patients, including from alcohol abuse, viral infection, or genetic defects. Irreversible liver dysfunction, such as what is found in some ALGS patients, requires liver transplantation. Strikingly, ~3,500 people are on the waiting list for a liver in California. While the number of people waiting for a liver transplant increases every year, the supply of available donor organs does not. This leads to longer waiting times, sicker patients, and decreased transplant success. Our work on the role cell-cell interactions and Notch signaling in liver development may ultimately identify novel ways to regenerate liver tissue and benefit these patients.

Thus, our experiments focusing on the role of Notch signaling in liver development may benefit a large number of patients in California beyond ALGS patients.