Principal Investigator: Ryan Shaw, PhD, Post-doctoral Scholar, Transplant Surgery Scientist Training Program, Northwestern Medicine, Northwestern University Feinberg School of Medicine Co-Principal Investigator: Richard M. Green, MD, Professor of Medicine (Gastroenterology and Hepatology), Northwestern Medicine, Northwestern University Feinberg School of Medicine Liver diseases such as primary sclerosing cholangitis (PSC) inflame and scar and block bile ducts, leading to back-up of bile in the liver and blood (jaundice) and prevent the normal secretion of bile into the intestines to aid digestion. Too much bile in the liver can lead to end-stage cirrhosis of this vital organ. Up to 85% of PSC patient also have ulcerative colitis or Crohn’s disease. With few effective treatments and no cure, adults and children with PSC and other cholestatic liver diseases face cirrhosis of the liver, liver failure and death without a liver transplant. Decades of work in the Green lab have shown in mouse models the protective influence of a gene in the liver called X-box Binding Protein 1 (XBP1). Because humans have different bile acids than mice, these species-specific differences limit the direct translation of mouse XBP1 cholestasis studies to corresponding human liver diseases. Granted the DHF award this year, the investigators plan to use two recently developed strains of “humanized” mice to investigate the role of XBP1 in a more human-like system. One producing humanized bile and the other, possessing humanized livers, these unique animal models will greatly aid in the development of novel drug or genetic therapies for PSC and other liver diseases that cause back-up of bile flow through the...
Principal Investigator: Dempsey L. Hughes, MD, Assistant Professor of Medicine (Gastroenterology and Hepatology), Northwestern Medicine, Northwestern Feinberg School of Medicine A new and aggressive form of chronic liver disease has developed in young adult survivors born with congenital, single ventricle heart disease. Until the 1970s, most babies born with essentially half a heart died in infancy until the introduction of a life-saving surgical technique called the Fontan procedure. While highly successful in correcting this cardiac defect early in life, the Fontan procedure has led to unanticipated, unfortunate outcomes – Fontan-associated Liver Disease (FALD) caused by abnormal blood flow in and out of the liver due to the heart disorder. FALD can progress from cirrhosis (irreversible liver scarring) to liver cancer, with the only cure being a massively risky heart transplant or combined heart-liver transplant. Accurate assessments of liver function could better guide treatment to improve the quality of life and survival of those developing FALD. Unfortunately, traditional liver MR imaging cannot be used in the presence of cardiac devices such as pacemakers, which many of these patients rely on. Thus, the best way of evaluating and tracking liver function in this at-risk population of Fontan patients is tragically unavailable due to their implanted medical devices that are saving their life. This year, a DHF award is supporting Dr. Hughes’ team in conducting a first-of-its-kind pilot on the use of endohepatology, a common upper endoscopy procedure, for liver disease staging in the FALD patient population. The researchers hope this novel use of endohepatology will greatly advance the clinical understanding of FALD by offering a vital alternative to MR imaging to...
Co-Principal Investigators: Xiaoying Liu, PhD, Research Assistant Professor of Medicine (Gastroenterology and Hepatology), Northwestern Medicine, Northwestern Feinberg School of Medicine Richard M. Green, MD, Professor of Medicine (Gastroenterology and Hepatology), Northwestern Medicine, Northwestern Feinberg School of Medicine A chronic disease of the liver that currently doesn’t have any treatment, primary sclerosing cholangitis (PSC) causes destructive scarring of the ducts that carry bile to the small intestine to help digest fats. Affecting some 50,000 Americans, PSC can occur alone, but is associated with ulcerative colitis or Crohn’s disease in 80% of PSC cases (Only about 6% of IBD patients have PSC). While the exact reason for this overlap still eludes scientists, thankfully, the inevitable progression of PSC toward cirrhosis is not worsened by IBD or treatment for IBD. Limited understanding of PSC has meant that, currently, there aren’t any effective medical therapies to stop dangerous disease progression. Ultimately, PSC patients develop liver cirrhosis, need a liver transplant, or die from their disease. X-box binding protein 1 (XBP1) is a protein that protects cells from injury. In previous studies, the Liu/Green team found in an animal model that when mice lacked XBP1 in their liver, they were more prone to develop liver damage. Granted the DHF award this year, the investigators plan to explore their hypothesis that progressive PSC results when the XBP1 signaling pathway fails to adequately activate to protect the liver. toThis study will be the first of its kind to use liver biopsies from patients with PSC to measure the XBP1 pathway in several different liver cell types injured by the disease. By identifying the role of XBP1...
THIS STUDY UTILIZES THE DHF BIOREPOSITORY Principal Investigator: Xiaoying Liu, PhD, Research Assistant Professor of Medicine (Gastroenterology and Hepatology), Northwestern Medicine, Northwestern Feinberg School of Medicine A rare liver disorder, primary sclerosing cholangitis (PSC) occurs when thickening of bile ducts block the normal, necessary flow of bile within the digestive system. Buildup of toxic bile acids can lead to irreversible liver cirrhosis, cancer, and the need for a risky, life-altering liver transplant. For unknown reasons, up to 70% of patients with PSC also have inflammatory bowel disease (IBD), especially ulcerative colitis. Today, effective treatments don’t yet exist to prevent this progressive and potentially fatal liver disease. Dr. Xiaoying Liu’s team is using this year’s DHF grant award to better understand the disease process of PSC in order to stop it from damaging the liver. The researchers are studying a molecular pathway called “unfolded protein response (UPR)” that springs into action to protect cells from toxicity in the liver. This exciting study stands on the shoulders of previously successful DHF funded research proving increased UPR pathway gene expression in post-liver transplant patients. Dr. Liu hopes to further delineate the protective role of UPR to create a first-in-the-world liver cell atlas in PSC to map cell signaling and cellular interactions. These studies offer important promise for identifying molecular targets to develop much needed new drug therapies for PSC...
THIS STUDY UTILIZES THE DHF BIOREPOSITORY Principal Investigators: Amanda C. Cheung, MD, Assistant Professor of Medicine (Gastroenterology and Hepatology), Northwestern Medicine, Northwestern Feinberg School of Medicine Andres Duarte-Rojo, MD, PhD, Professor of Medicine (Gastroenterology and Hepatology) and Surgery (Organ Transplantation), Northwestern Medicine, Northwestern Feinberg School of Medicine A serious public health concern, excessive alcohol consumption causes almost 50% of liver disease deaths in the United States. Unfortunately, many patients with alcohol-associated liver (ALD) damage have late stage disease by the time they receive a diagnosis. A major liver transplant is often their only option for lifesaving treatment. Importantly, the relationship between amounts of alcohol consumed and damage to the liver is difficult to predict, with some patients (often women) developing liver scarring earlier with less alcohol consumption while others are able to drink more without significant health complications. To add to this challenge, no detection tests currently exist to identify early signs of liver scarring (fibrosis) in individuals with alcohol use disorder. This year, a DHF award is supporting Dr. Amanda Cheung’s team in identifying a biomarker for early fibrosis to improve ALD screening for at-risk individuals. A network of proteins and molecules surrounding cells, the extracellular matrix (ECM) may offer promise as an early warning system. Inflammation from ALD has been shown to damage the ECM, increasing detectable chemical changes, or “degradome,” that are precursors to developing irreversible fibrosis. Up to this point, limited studies have looked only at the degradome profiles in the blood of patients with liver fibrosis. In this new DHF study, Dr. Cheung’s team is investigating the degradome profiles of patients with ALD before...
