Funded Research

Discovering Novel Therapeutic Interventions for Alpha-1-antirypsin Deficiency Liver Disease
Principal Investigator(s):
  • David Rudnick, M.D., Ph.D. Pediatrics Visit Website
  • Stephen Pak, Ph.D. Pediatrics
  • Center for Metabolism and Immunity
Award Mechanism:
Interdisciplinary Research Initiative
Project Period:
2/1/2017 - 1/31/2019
Total Amount:

Brief background of the proposal and its relevance to the CDI’s objectives

α1-antitrypsin deficiency (ATD) causes significant childhood liver disease and is the most frequent genetic indication for pediatric liver transplantation. ATD liver disease occurs because the mutant, cytotoxic α1-antitrypsin protein (ATZ) accumulates in hepatocytes, but only a subset of patients carrying the disease-causing mutation develops liver disease. Because modifiers of ATZ accumulation determine ATD liver disease risk, targeting those modifiers could lead to novel ATD therapies. Recent analyses showed that genetic disruption of hepatic insulin signaling reduces ATZ accumulation in C. elegans and improves ATD liver disease in mice. This project proposes that suppressing downstream insulin signaling intermediaries could be therapeutic for ATD liver disease.

Proposed specific aims

·         Interrogate the effects of drugs that suppress hepatocellular insulin signaling intermediaries for effects on experimental ATD liver disease in mice.

·         Screen transgenic ATZ-expressing C. elegans strains with drug libraries to identify candidates that reduce ATZ accumulation by targeting downstream insulin signaling mechanisms.

Potential impact on child health

These studies are relevant to the CDI Metabolism Center’s mission, and in the long-term, the results could be translated into pediatric ATD liver disease intervention trials.