2024 Grant Awards

2024 Grant Awards

International Validation of Serum Protein Biomarkers for Predicting and Early Diagnosing Cholangiocarcinoma (CCA) in Individuals with Primary Sclerosing Cholangitis (PSC)

Principal Investigator: Jesus Banales, Ph.D. 

AWARD: $60,000

Project Summary: PSC presents a significant risk for CCA, the leading cause of premature death in this population. Currently, PSC is the sole condition subject to routine CCA screening. However, the existing clinical workflow for non-invasive CCA diagnosis in individuals with PSC often falls short in early detection due to overlapping features between benign and malignant biliary strictures. In a recent international study [Lapitz A,..., Banales JM. Journal of Hepatology 2023], we demonstrated that serum EVs harbor protein biomarkers enabling accurate prediction and early diagnosis of PSC-associated CCA, detectable using total serum. Notably, the combination of CRP/FIBRINOGEN/FRIL allows specific early CCA diagnosis in individuals with PSC, outperforming the serum tumor marker CA19-9. Moreover, the levels of CRP, FIBRINOGEN, FRIL, and PIGR enable the prediction of CCA development in individuals with PSC before any clinical evidence of malignancy, facilitating risk stratification. In this research proposal, our objective is to internationally validate these findings using the cost-effective and easily transferable ELISA technique, taking a step forward in translating these novel biomarkers into clinical practice. To achieve this, we have already collected over 300 serum samples from international reference centers (from IPSCSG and ENSCCA) across four study groups with fully annotated clinical data: i) healthy individuals; ii) isolated PSC (with no CCA development >5 years); iii) PSC before CCA development; iv) PSC with CCA (PSC-CCA). The project aims to develop innovative liquid biopsy tools for PSC surveillance programs, enabling CCA risk stratification and early detection, and facilitating personalized treatment plans. The ultimate goal is to enhance patient well-being and increase survival rates.

Biomarkers for Risk Stratification in Primary Sclerosing Cholangitis (PSC)

Principal Investigator: Prof. Johannes R. Hov, M.D. Ph.D. 

AWARD:  $60,000

Project Summary: In the present project an experienced international research team will measure several blood markers of the disease severity and activity in PSC. This we will do in the context of the International PSC Study Group, using already collected material from a large international study (>10 countries) where people with PSC were followed for >5 years with repeated measurements of liver stiffness. Of particular interest is the measurement of the commercially available blood test ELF, which reflects scarring activity (fibrosis) in the liver, to define to what degree this blood test can be used to predict disease outcome over time, as well as disease progression from year to year. Furthermore, the same material will be used to further investigate other promising blood tests to understand whether they tell us more about the disease than ELF and liver stiffness measurements, and hopefully selecting some for further development into a combined blood test available for patient care in the clinic.

Portal Fibroblasts as Targets to Limit Liver Fibrosis in PSC

Principal Investigator: Sara Lemoinne, M.D, Ph.D. 

AWARD: $80,000

Project Summary: The goal of our research project is to better understand the signals and processes leading to scar tissue deposition in primary sclerosing cholangitis (PSC). Notably, we focus our research on portal fibroblasts, which are liver cells lying in the vicinity of damaged bile ducts, and molecular triggers that induce disease matrix production by these cells. To do this, we use genetically modified mice to either track portal fibroblasts with a special fluorescent protein that marks these cells during the scarring process or to specifically remove these cells to see how the scarring process is affected. We are also dedicated to identifying genes in portal fibroblasts that can represent sensitive and specific markers that would be associated with liver scarring. Once identified in mice, these genes will be analyzed in liver samples from PSC patients to see if they can translate to human setting and predict severity of the disease. We will also look at signals arising from the gut that affect these portal fibroblasts. We will study how gut inflammation, levels of these cells, and signals from the gut are connected in PSC patients. By the end of this research, we hope to understand how these specific liver cells contribute to the scarring process in PSC. This knowledge could lead to new treatments for liver scarring in PSC patients.

The Transcription Factor RUNX1 is Pivotal in TGFβ-activated Cholangiocyte Signaling with the Immune System in PSC

Principal Investigator: Sayed Obaidullah Aseem, Ph.D., M.D. 

AWARD: $80,000

Project Summary: Primary sclerosing cholangitis (PSC) is characterized by scarring around the bile ducts, termed biliary fibrosis. This is the predominant pathological process that results from the signaling interactions between cholangiocytes that line the bile ducts, immune cells, and myofibroblast-type cells that are activated to produce the fibrosis. Signals produced by cholangiocytes are likely to be critical in these communications and driving both inflammation and fibrosis. Based on our previous studies, we have identified a transcription factor, RUNX1, that is likely to be critical in these processes and is increased in the liver of PSC patients. Our preliminary data show that inhibition of RUNX1 results in reduced inflammatory signals by cholangiocyte cell models. In a mouse model, inhibition of RUNX1 results in reduced immune/inflammatory cell accumulation around the liver bile ducts. We propose studies to determine in detail the mechanisms involving RUNX1 and whether RUNX1 directly interacts with a master regulator of inflammatory signals. We also plan to use mouse genetic models to genetically delete RUNX1 in cholangiocytes selectively and test the effect of RUNX1 deletion on biliary fibrosis and inflammation around the bile ducts. We hope that understanding how RUNX1 and its downstream partners regulate the production of cholangiocyte signals that give rise to inflammation and fibrosis will allow us to identify therapeutic targets for PSC.

Molecular Mechanisms Regulating Neutrophil-Induced Oxidative Stress in Primary Sclerosing Cholangitis (PSC)

Principal Investigator: Nidhi Jalan-Sakrikar, Ph.D. 

AWARD: $60,000

Project Summary: PSC is a complex progressive liver disease characterized by chronic inflammation of bile ducts. Persistent inflammation can lead to liver damage through scarring that leads to fibrosis and cirrhosis. Neutrophils are the most abundant white blood cells in humans and have been well established as first responders to acute inflammation. Under normal conditions, neutrophils contribute to tissue repair and inflammation resolution. However, in chronic diseases, infiltrated neutrophils are exposed to inflammatory conditions in the tissue that impacts their properties which can lead to reduced pro-resolving function thereby causing tissue damage. Bile duct cells isolated from PSC patients had increased number of associated neutrophils compared to those from non-PSC control patients. In this proposal we aim to investigate the mechanism responsible for the observed neutrophil infiltration. We also plan to examine the impact of the infiltrated neutrophils on the bile duct cells and how the association with bile duct cells can influence changes in neutrophils. Furthermore, in our preclinical animal models of PSC we will employ pharmacological inhibitor and neutralizing antibody approach thereby interfering with neutrophil infiltration to investigate its therapeutic potential in reducing chronic liver inflammation and fibrosis.

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