2022 PSC Partners Research Grants Program Update
Four research teams were recently awarded funding to drive research to identify treatments and a cure for PSC. The awards were given in 2022, and the research will commence in 2023. Read on for a summary of each project:
Hepatic Unfolded Protein Response (UPR) in Murine Models of PSC - Lead Investigator: Young Investigator Alyssa Kriegermeier, MD, Northwestern University Feinberg School of Medicine
AWARD: $80,000 over two years (Young Investigator Award)
Cholestatic liver diseases, including PSC, are a significant cause of morbidity within the field of pediatric hepatology and are the leading indication for pediatric liver transplantation. There are no effective medical treatments for pediatric PSC, or the majority of pediatric cholestatic diseases, that decrease the need for transplantation. As a Pediatric Transplant Hepatologist, I understand that therapies that can prevent or delay the need for transplant are desperately needed for both pediatric and adult PSC patients. The lack of effective therapies is, in part, due to the inadequate understanding in how the liver reacts to bile acid induced liver injury including the liver cell’s activation of the unfolded protein response (UPR). The accumulation of toxic bile acids (as occurs in PSC) is known to trigger endoplasmic reticulum (ER) stress, which describes the accumulation of misfolded/unfolded proteins. The UPR is a protective molecular response that decreases ER stress. Our laboratory’s preliminary data has demonstrated that knocking out UPR pathways in mice fed bile acids leads to worse injury, however paradoxically in the Mdr2-/- mouse model of PSC, knocking out this same pathway is protective and is associated with decreased hepatic bile acids. The goal of this study is to identify the role of these pathways in liver injury during cholestasis and bile acid metabolism. Through parallel studies in murine models of PSC we will identify the UPR-specific pathways which influence disease progression in response to cholestasis-induced ER stress and hope to find new therapeutic targets for patients with PSC.
Novel Proteome-Wide Autoantibody Discovery in Primary Sclerosing Cholangitis - Lead Investigators: Young Investigator Michael Li, MD, PhD and Joseph DeRisi, PhD, University of California, San Francisco
AWARD: $80,000 over two years (Young Investigator Award)
A major unmet clinical need in primary sclerosing cholangitis (PSC) is that no circulating autoantibodies have thus far been identified that can be used to guide diagnosis or prognosis. In fact, the American and European liver disease societies both recommend against the use of currently-known antibodies for diagnostic purposes. This is unlike many immune-mediated diseases including the other autoimmune liver diseases (primary biliary cholangitis and autoimmune hepatitis), for which autoantibody testing is part of standard of care. We propose utilizing a new technology called Phage Immunoprecipitation Sequencing (PhIP-Seq), which allows us to study the unique antibodies in a given patient population by testing their ability to bind to the approximately 20,000 proteins that are produced by the human body. We will collect blood samples from patients enrolled in our study and apply PhIP-Seq in order to discover new PSC-associated antibodies. In addition to providing physicians with better tools to diagnose PSC, we hope that these antibodies will also shed light on how PSC develops and direct future novel PSC therapies.
Unraveling the Immune Triggers of Primary Sclerosing Cholangitis With and Without Concomitant Inflammatory Bowel Disease - Lead Investigator: Prof. Rinse K. Weersma, MD, PhD, University Medical Center Groningen, The Netherlands
AWARD: $60,000 over two years
The human gut contains a vast collection of bacteria and other microorganisms that can be both beneficial and detrimental to health. Our immune system is designed to sense these gut microbes and controls the dynamic interactions between ourselves and the residing microorganisms. Some immune responses to gut microbes may contribute to health, whereas others might trigger or exacerbate inflammatory diseases such as primary sclerosing cholangitis (PSC) with or without inflammatory bowel disease (IBD). In this project, using an innovative sequencing technology, we aim to comprehensively characterize the antibody epitope repertoire of patients with PSC and explore the interactions between antibodies and the gut microbiota, allergens, and immune proteins. Following this, we aim to generate an “immunological fingerprint” that may inform us about the development and progression of PSC.
Targeting PSC Pathogenesis Using a Bifunctional Peptide, GP119, in the Mdr2-/- Mouse Model of PSC and Novel Multicellular Human-Derived 3D PSC Organoids - Lead Investigators: Heather Francis, PhD, FAASLD and Gianfranco Alpini, PhD, Indiana University
AWARD: $60,000 over two years
PSC is characterized by ductular reaction (expansion of bile ducts), inflammation and liver fibrosis. There are several models used to study PSC including animal models (Mdr2-/- mice) and liver organoids. Developing drugs for human use is critical to offer relief from the debilitating symptoms and PSC disease progression. GP119 is approved for phase 1 clinical studies in Canada Health and our studies in both the mouse model of PSC and in human PSC-derived organoids will support the use of GP119 in a potential phase 2 clinical trial in PSC patients. The experiments proposed using human-derived 3D organoids will also allow us to examine the effects of GP119 in a liver microenvironment with potential for personalized medicine applicability.
(This project is supported by PSC Partners Canada.)
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