In 2009, PSC Partners Seeking a Cure awarded its first set of research grants. For PSC Partners, this was a milestone, an important step towards taking us closer to new treatments and an eventual cure. PSC Partners Canada joined the grants program in 2016. Since the inception of the program, together, over CAD $4,000,000 has been allocated to promising PSC research projects (as of Feb 2020). The Canadian affiliate grants made currently total CAD $395,000.
We thank our Canadian donors who have supported our mission of raising funds to research causes, treatments and cures for primary sclerosing cholangitis. Your contributions have made these awards possible.
To see a record of all research funded by both US-based PSC Partners Seeking a Cure and PSC Partners Canada, please visit here.
Listed below are awards funded by PSC Partners Canada.
- PSC Partners Canada Fellowship in PSC and Autoimmune Liver Disease: a clinical and research fellowship in primary sclerosing cholangitis (PSC) for a period of one year at the direction of Dr. Aliya Gulamhusein and Dr. Gideon Hirschfield in the Toronto Centre for Liver Disease at University Hospital Network (Toronto Centre for Liver Disease) (award matched for a 2nd year by Toronto General and Western Hospital Foundation)
- CASL PSC Partners Seeking a Cure Canada Award to Dr. Julian Hercon for the best abstract on PSC presented at Canadian Liver Meeting: Evolution of autoimmune cholangitis and primary sclerosing cholangitis in a pediatric cohort. J. Hercun, P. Willems, F. Alvarez (Awarded through Canadian Association for the Study of Liver Disease)
- PSC Partners Canada Research fellowship in primary sclerosing cholangitis (PSC) for a period of one year at the direction of Dr. Sonya MacParland in the Soham & Shaila Ajmera Family Transplant Centre at University Hospital Network. The fellow to focus on basic research to identify cellular mediators of PSC pathogenesis and targetable immunological defects that underlie the progression of PSC. (award matched for a 2nd year by Toronto General and Western Hospital Foundation)
- PHENOTYPES OF PATIENTS WITH RECURRENT PSC AFTER LIVER TRANSPLANTATION: AN INTERNATIONAL NETWORK STUDY Aliya Gulamhusein, MD, MPH, FRCPC, Assistant Professor, University of Toronto, Clinical Investigator, Toronto General Hospital, Toronto Centre for Liver Disease, Toronto, Ontario, Canada, Amount Awarded: USD $80,000 over two years, Project Summary: Recurrent PSC (rPSC) is a distressing complication that occurs in some PSC patients post liver transplantation and is associated with a four-fold increased risk of graft failure or death. This research is directed at developing an improved understanding of clinical and immunopathogenic pathways underpinning recurrent PSC. We aim to comprehensively characterize (phenotype) a prospective cohort of patients with PSC post liver transplant and use newly emergent mass cytometry technology to understand clinical, serologic, microbiological, and immunologic changes associated with development of rPSC. In addition, we will establish an international network among liver transplant centers worldwide to characterize clinical risk factors associated with rPSC. Results of this research will improve understanding of disease pathogenesis, and may also illuminate “immune signatures” associated with outcomes and thus has potential to identify targets for therapy. This disease is devastating to patients and their families, is costly to the health care system, and is a critical unmet need. Identifying clear risk factors for rPSC requires a systematic and comprehensive phenotypic evaluation of patients to identify those in greatest need of targeted early intervention.
- INTEGRIN AVB6 AS A THERAPEUTIC TARGET FOR PRIMARY SCLEROSING CHOLANGITIS – ASSOCIATED CHOLANGIOCARCINOMA Yury V. Popov, MD, PhD, Director, Liver Fibrosis Research, Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, Amount Awarded: USD $60,000 over two years. Project Summary: Cholangiocarcinoma (CCA) is a liver and bile duct cancer of unknown cause and rising incidence worldwide. CCA is a devastating complication of PSC, difficult to diagnose and associated with high mortality. Treatment options are extremely limited as PSC-associated CCA patients often do not qualify for liver transplantation. In the absence of drug options in the treatment of PSC-associated CCA, poor prognosis and high mortality, new therapeutic approaches are urgently needed. Integrin αvβ6 is an epithelial tissue cell surface receptor which is virtually absent from normal livers. It has been shown to be markedly upregulated on activated bile duct epithelial cells and liver cells with features of ductular transformation, correlating with fibrosis stage, both in rodent models of fibrosis and in patients with chronic liver disease. Integrin αvβ6 binds and activates transforming growth factor beta and is expressed on liver progenitor cells that are linked to both biliary fibrosis and the formation of cancer. This study proposes to develop a model of CCA in a mouse model of PSC (mdr2-/- ) and to assess the impact of integrin αvβ6 on the development of CCA and possible therapeutic potential of drugs targeting this pathway. Since several αvβ6-specific inhibitors are currently at various stages of drug development for other indications, rapid translation of findings into clinical practice is feasible. Completed Study (2019) Update: In the first year, a new mouse model of cholangiocarcinoma (CCA) was established on PSC-like Mdr2-/- background, termed SB CCA.Mdr2-/- model. Susceptibility to CCA in this system is driven by the biliary injury and fibrosis in Mdr2-/- mice, recapitulating the predisposition to biliary cancer in human PSC. Most of CCAs arising in SB CCA.Mdr2-/- mice express various levels of αvβ6 integrin. In the second year, we refined the model characterization by replication (and thus increasing the samples size to at least 9 mice/group), and performing long-term survival analysis and interrogated the influence of common laboratory mouse genetic backgrounds (FVB, C57Bl/6, BALB/c) on CCA susceptibility and growth. These tests confirmed 1) model reproducibility, 2) major differences in tumorigenesis observed between healthy and fibrotic hosts, and 3) established the surrogate and hard end-points for future therapeutic efficacy tests. Further, we utilized T- and B- cell deficient Mdr2-/-;Rag1-/- double-mutants to demonstrate that adaptive immunity functionally restricts CCA growth, suggesting that our model is suitable for testing novel immunotherapies. Ongoing experiments interrogate the role of αvβ6 and related integrins as a potential therapeutic target in PSC-associated CCA using genetic and pharmacologic approaches in the SB CCA.Mdr2-/- model. We are preparing manuscript describing the model and develop several grant applications, both NIH and industry-sponsored, that directly stem from research supported by this grant.
- THE ENTEROHEPATIC METABOLOME IN PRIMARY SCLEROSING CHOLANGITIS Steven P. O’Hara, PhD, Assistant Professor of Medicine and Biochemistry/Molecular Biology, Mayo Clinic, Rochester, MN, USA Amount Awarded: USD$60,000 over two years. Project Summary: Emerging data, including work from our laboratory and clinical research group, suggest fundamental disease associated mechanisms in primary sclerosing cholangitis (PSC) that are centered on molecules derived in the gut and brought to the liver through portal circulation (gut-liver axis). The gut-liver axis has been proposed to play a significant role in the initiation, progression, and adverse clinical events associated with PSC; however, this has not been directly tested to date. Our goal is to determine whether there are differences in the metabolites (proteins, fats, and other chemicals) in the portal vein (which delivers blood from the intestines to the liver) and in bile between individuals with primary sclerosing cholangitis and those without PSC. We anticipate that patients with PSC will have distinct alterations in the portal venous and bile metabolites compared to controls; and these alterations may be amenable to future therapies.