Previous Grants

PSC Partners Annual Research Grant Awards

PSC Partners Seeking a Cure held its first competition for research grants in January, 2009. Click here for the research proposal application materials.

In its first competition PSC Partners Seeking a Cure made eight awards. We thank everyone who has contributed funds to PSC Partners Seeking a Cure. Your contributions have made these awards possible!

Proposals were reviewed by the Scientific/Medical Advisory Committee: Dr. Dennis Black, Dr. Chris Bowlus, Dr. Kapil Chopra, Dr. Steven Deitch, Dr. Greg Everson, Dr. Aubrey Goldstein, Dr. Richard Green, Dr. Denise Harnois, Dr. Gideon Hirschfield, Dr. Johannes Hov, Dr. Keith Lindor, Dr. Stephen Miller, David Rhodes (Chair), and Dr. Don Safer. In total, PSC Partners Seeking a Cure has invested $317,706 in PSC research. Grant awards are made on an annual basis.

Awarded in 2009

Eight awards were selected for funding from 24 grant applications. The grants are funded for two years each.

• Examining the Disease Impact of Genetic Variation in Logical Candidate Genes for PSC: a PROGRESS Study.

  Konstantinos N. Lazaridis, M.D., Assistant Professor of Medicine, Center for Basic Research in Digestive Disease, Mayo Clinic College of Medicine 200 First Street SW, Rochester, MN 55905.

  Project Summary: Genetic predisposition is thought to play a key role in the susceptibility to primary sclerosing cholangitis (PSC). However, the rarity of PSC has rendered the collection of sufficient multiply-affected families to perform traditional genetic analyses impossible, hampering efforts to identify the associated genetic variants. To this end, we established the PSC Resource Of Genetic Risk, Environment and Synergy Studies (PROGRESS) registry and biorepository, a national research resource aimed at elucidating the genetic and environmental contributors to PSC by combining association-based study designs with cutting-edge and emerging approaches to their analysis. We are now in the position to utilize PROGRESS for genetic studies and have elected to focus on highly selected, biologically plausible candidate genes. This logical candidate gene approach remains important in the era of genome-wide studies as it provides for superior gene coverage and a more subtle appreciation of disease affects for these highly suspect genes than afforded by the more comprehensive studies. Moreover, this genetic information may prove valuable to future gene-gene and geneenvironment interaction studies, even when no primary association is identified.

  Our seminal effort has identified a strong association between PSC and a promoter polymorphism in the tumor necrosis factor alpha (TNFalpha) gene. Here we propose to build upon this finding by genotyping haplotype tagging single nucleotide polymorphisms (SNPs) in a number of PSC candidate genes, performing association analysis for disease status as well as subphenotypes of disease, and exploring potential gene-gene and gene-environment interactions by utilizing the unique resource available to us in the PROGRESS registry and biorepository.

• Cholangiocarcinoma-associated serum microRNAs in primary sclerosing cholangitis: Identification and prognostic potential.

  Pietro Invernizzi, M.D., Ph.D., Assistant Professor of Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis GBSF suite 6515, Davis, CA 95616. [Collaborators: Kirsten M. Boberg, M.D., Ph.D. (Medical Department, Rikshospitalet University Hospital, Oslo, Norway); Gianfranco Alpini, Ph.D. (Research, Central Texas Veterans Health Care System and Department of Medicine, Central Texas Veterans HCS and Texas A&M HSC COM, Scott & White Hospital, Temple, TX); Antonio Benedetti, M.D. (Department of Gastroenterology, University “Politecnica delle Marche”, Ancona, Italy); Domenico Alvaro, M.D. (Department of Gastroenterology, Universita “La Sapienza”, Roma, Italy); Guido Torzilli, M.D. (Liver Surgery Unit, Department of Gastroenterology, IRCCS Istituto Clinico Humanits, University of Milan, Rozzano, Italy)]

  Project Summary: Primary sclerosing cholangitis (PSC) is associated with a high risk of cholangiocarcinoma (CCA), a rare but often fatal malignancy of the bile duct epithelium. Several tumour markers have been used to aid diagnosis, but no useful markers specific for CCA are currently available. Because of the ease of obtaining blood samples, there is an obvious need for accurate serum markers for screening of CCA in PSC patients at an early stage of this cancer or, even better, for pre-cancer biomarkers. MicroRNAs (miRNAs) are a group of endogenous small non-coding RNAs involved in the control of cell differentiation processes, and consistently with this they have been demonstrated to be useful cancer biomarkers. Recently, this emerging field of study has discovered that miRNAs can also be efficiently evaluated in serum. The aim of the project is to identify specific serum miRNAs with a role as pre- or early-cancer biomarkers for human CCA in patients with PSC. The project will be divided in two phases: (i) In the first phase (first year) we will investigate the miRNAs expression profile (1) in available serum from 30 patients with CCA, 30 with PSC, and 30 healthy subjects, matched by sex and age to CCA patients, (2) in five human CCA immortalized cell lines and one normal immortalized biliary epithelial cells (BECs) line, and (3) in available human primary BECs cultures from CCA, PSC and normal subjects (ii) In the second phase (second year) we will take advantage of an extraordinary unique multi-center series of PSC sera (n=400) collected in tertiary referral liver centers in USA, Italy, and Norway in order to evaluate with a longitudinal (retrospective/prospective) study the role as pre- or early-cancer biomarkers of the CCA-specific miRNAs identified in the phase 1 of the study.

• Aberrant homing of lymphocytes to the liver in patients with primary sclerosing cholangitis; the missing link between colon and liver.

  Cyriel Y. Ponsioen, MD, PhD, Department of Gastroenterology & Hepatology, Academic Medical Center, C2-112, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. [Collaborators: Kirsten Boonstra, Ph.D. student, Department of Gastroenterology & Hepatology, C2-231; Anje A. te Velde, Ph.D., Department of Experimental and Molecular Medicine, H2-256; Prof. Ulrich Beuers, M.D. Ph.D., Department of Gastroenterology & Hepatology, Academic Medical Center, C2-321, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands]

  Project Summary: Primary sclerosing cholangitis (PSC) is a rare chronic inflammatory disease of the biliary tree leading to bile duct strictures, to fibrosis and cirrhosis of the liver and eventually to liver failure. The etiopathogenesis is unknown. There is no medical therapy of proven benefit for the long-term prognosis so far. Liver transplantation is the treatment of choice in late stage disease. PSC is highly associated with inflammatory bowel disease (IBD). It was proposed that T lymphocytes primed to home to gut tissue, by mistake instead home to the liver in PSC, thereby keeping the chronic inflammation ongoing. It was hypothesized that erroneous homing of gut-primed lymphocytes in PSC is caused by aberrant over-expression or functioning of the chemokines, integrins, or addressins involved in transendothelial migration of gut-homing T-cells. We hypothesize that this may occur through functional gene mutations.

  The topic of our research project is to study location-specific expression of these chemotactic molecules in PSC, in particular to prove that there is colonic expression of CCL25.

  A cohort of greater than 400 PSC patients with detailed phenotyping and appropriate controls (primary biliary cirrhosis, IBD-patients and healthy partners) is being accrued from 42 hospitals in central-Netherlands. The expression of CCL25, CCR9, alpha4Beta7, and MAdCAM-1 will be studied as candidate chemotactic factors in cases and controls by immunohistochemical expression in PSC liver and colon tissue, as compared to control tissues. Peripheral blood and colonic lamina propria lymphocytes (PBL and LPL) will be harvested and analyzed by FACS to examine the expression of CCR9 and alpha4Beta7.

  Potential relevance of our research will be 1. to ascertain the gut-homing lymphocyte paradigm in the IBD-PSC association; 2. to assess the presence of PSC associated gut-homing chemokines, addressins and integrins in colonic tissue; 3. to pinpoint the role of CCL25, CCR9, alpha4Beta7, and/or MAdCAM-1 in the pathogenesis and/or sustaining of inflammation in PSC. This will lend support to initiate trials in PSC with specific inhibitors of gut-homing chemotaxis such as natalizumab and Traficet; 4, the building of a large population-based PSC cohort including biobanking for future studies.

• alpha4Beta7-Integrin Ligand Development for the Treatment of PSC.

  Christopher Bowlus, M.D., Associate Professor, Division of Gastroenterology, UC Davis Medical Center, 4150 V Street, PSSB 3500, Sacramento, CA 95817 [Collaborators: Ruiwu Liu, Ph.D. Assistant Research Chemist, University of California, Davis, 2700 Stockton Blvd., Suite 1400, Sacramento, CA 95817; Kit S. Lam, M.D., Ph.D., Professor and Chief, Division of Hematology and Oncology, UC Davis Cancer Center, 4501 X St., Sacramento, CA 95817; Mark Kurth, Ph.D., Professor, Department of Chemistry, University of California, Davis, CA 95616; Yoshikazu Takada, M.D., Ph.D., Professor, Department of Dermatology, University of California Davis Medical Center, Research III Suite 3300, 4645 2nd Avenue, Sacramento, CA 95817]. $40,000 over 2 years.

  This project will be entirely funded by a generous donation from Abe and Rachel Gomel.

  Project Summary: Primary sclerosing cholangitis (PSC) is due in part to gut-derived lymphocytes trafficking to the liver in response to specific adhesion molecules and chemokines normally expressed in the gut. Specifically, alpha4Beta7-integrin expressing lymphocytes home to the PSC liver where its ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is aberrantly expressed. Blocking alpha4 integrins has been successfully targeted by monoclonal antibodies for the treatment of Crohn’s disease. However, the use of this therapy in PSC is hindered by the risk of progressive multifocal leukoencephalopathy (PML), believed to be due to the lack of specificity for alpha4Beta7. Vedolizumab (formerly known as MLN002 and MLN02), is a monoclonal antibody with specificity for alpha4beta7 that has shown efficacy in phase 2 clinical trials of moderately active ulcerative colitis and Crohn’s disease. However, monoclonal antibodies have limitations. The antibody molecule is relatively large with a molecular weight of 160,000 kD requiring infusion or subcutaneous injection. In addition, even with humanized forms of these monoclonal antibodies, human anti-chimera antibodies (HACA) are frequently generated and are sometimes associated with a lower rate of response. Peptides are considerably smaller than monoclonal antibodies and generally do not illicit a humoral immune response. They are chemically stable and relatively easy to derivatize. Although peptides are susceptible to proteolytic degradation in vivo, this can be inhibited with blocking of their N- and C-termini, making them cyclized, or incorporating D-amino acids. 
In this proposal, we will take advantage of our expertise in One Bead-One Compound (OBOC) combinatorial chemistry, integrin biology, immunology and PSC to identify novel lead compounds for the treatment of PSC. We have previously identified a high affinity, high specificity peptidomimetic ligand for alpha4Beta1-integrin that is currently under pre-clinical development. In this project we will use the same technology to identify lead compounds for alpha4Beta7 ligands. In Aim 1 we will design and synthesize a diverse combinatorial chemistry library based upon the known alpha4Beta7 binding motif. In Aim 2 we will use a whole cell method to screen this library with alpha4Beta7+ T cells from PSC patients. The specificity and binding affinity of these lead compounds will be assessed in Aim 3. Upon completion of this project we will have identified lead compounds that will be ready to proceed to functional testing. In addition, the knowledge gained will be used to design focused libraries which will be screened for additional ligands.

• Non-invasive Assessment of Disease Progression in Primary Sclerosing Cholangitis.

  Gregory T. Everson, M.D., Transplant Center and Hepatology, Clinic Mail stop B, 154 Anschutz Outpatient Pavilion, 1635 N. Ursula Street, Room 7085, Aurora, CO 80045. [Collaborators: Steve Helmke, Ph.D.; Lisa Forman, M.D.]. $40,000 over 2 years.

  Project Summary: Current methods for monitoring primary sclerosing cholangitis (PSC) disease progression are insensitive, invasive, and nonspecific. We have developed a novel noninvasive technique to accurately measure liver function by quantifying portal-systemic shunting, the cholate shunt test. Our overriding hypothesis is that our liver function test will accurately monitor PSC disease progression.

• The Role of Abcb11 and Fibroblast Growth Factor 15/19 in the Pathogenesis of Primary Sclerosing Cholangitis.

  Richard M. Green, M.D., Associate Professor of Medicine, Division of Hepatology, Northwestern University Feinberg School of Medicine. $40,000 over 2 years.

  The first year of this project will be funded by a generous donation from Ros and David Parry.

  Project Summary: Primary sclerosing cholangitis (PSC) is a hepatic disease of unknown etiology that can lead to cirrhosis, cholangiocarcinoma and the need for liver transplantation. It is characterized by inflammation and fibrosis of cholangiocytes, the cells that compose the liver bile ducts. Unfortunately, no effective therapy has been shown to slow disease progression, in part because the pathogenesis of primary sclerosing cholangitis remains poorly understood. By enhancing our understanding of the pathogenesis of PSC, one can better design rational therapies for this potentially devastating form of chronic liver disease. 
The cholangiocytes that form the bile ducts are exposed to extremely high concentrations of bile salts, which induce signaling changes in cholangiocytes. The high bile salt concentrations in bile are created by the ATP-dependent secretion of bile salts from the liver into the biliary system. Our laboratory has a long-standing interest in identifying the mechanisms by which hepatocytes (liver cells) secrete bile salts into the biliary system. We, along with other investigators, have determined that bile salts are secreted by the liver canalicular membrane transporter Abcb11. Furthermore, we have cloned Abcb11 and developed a transgenic mouse that over-expresses Abcb11 in the liver. In addition, the level of expression of Abcb11 in humans is highly variable (by a factor of over 10) and therefore it is likely important in the manifestation of many cholestatic liver diseases. However, the impact of high levels of Abcb11 expression on primary sclerosing cholangitis is poorly understood. 
A recently identified gut-derived hormone named fibroblast growth factor 15/19 (FGF15/19) is secreted by the ileum in response to bile salt stimulation and subsequently interacts with hepatocytes and cholangiocytes to regulate their function and maintain normal cellular homeostasis. Although FGF15/19 has been shown to be an important physiologic regulator of ductular cells in the gallbladder and for gallstone formation, the function of FGF 15/19 in other biliary tract diseases remains unknown. In the proposed studies, we will explore the role of Abcb11 and FGF 15/19 in biliary tract disease; since our enhanced understanding of these physiologic processes will allow for the design of rational, novel therapeutic targets for treating patients with PSC

• A Pilot study of Vancomycin or Metronidazole in patients with Primary Sclerosing Cholangitis.

  Keith D. Lindor, M.D., Mayo Clinic, 200 First Street, SW, Rochester, MN 55905. [Collaborators: Marina G. Silveira, M.D.; Andrea Gossard, C.N.P.; Roberta Jorgensen, R.N.; Jill C. Keach; Janice Petz, R.N., Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota]. $25,706 over 2 years.

  Project Summary: Primary Sclerosing cholangitis (PSC) is a progressive liver disease without effective medical treatment. Although treatment with ursodeoxycholic acid (UDCA) improves serum liver tests and is prescribed frequently for PSC patients, this drug appears to have no beneficial effect on the course of the disease. Recent results of UDCA used in high doses have been most disappointing. 
Various antibiotics have been tested sporadically for the treatment of PSC over the years with promising results reported. The numbers of cases were small, sometimes single case reports, and the duration of follow up has been variable but often short. In the current protocol, we propose the assessment of potential beneficial effects of the antibiotics vancomycin and metronidazole on liver biochemistries, liver related symptoms and Mayo risk score in 40 patients with PSC. The patients will be randomized into four groups of ten patients: one group will receive low dose vancomycin, one group will receive high dose vancomycin, one group will receive low dose metronidazole and one group will receive high dose metronidazole. Each group will be treated for three months. Liver biochemistries, C-reactive protein (CRP) and Mayo risk score will be determined at three weeks and three months and compared to baseline values as well as values at 3 months in the placebo group (n=74) from the recent high dose UDCA study. A positive study based on significant liver biochemical improvement will establish the basis for further evaluation of one or both antibiotics in a larger number of patients for a longer time period within a randomized controlled trial.

• Quality of life in patients with primary sclerosing cholangitis.

  Gideon Hirschfield, MA MB BChir MRCP PhD, Assistant Professor of Medicine, University of Toronto, Liver Centre, Toronto Western Hospital 399 Bathurst St, 6B Fell, Rm 162, Toronto, ON, M5T 2S8, Canada. [Collaborators: Natasha Chandok, MD FRCPC, Adjuvant Professor of Medicine, University of Western Ontario; Maria Cino, MD FRCPC, Assistant Professor of Medicine, University of Toronto]. $10,000 over 2 years

  This project will be funded in large part by a generous donation from Hoops 4 Healing  (http://www.hoops4healing.org/).

  Project Summary: We aim to prospectively evaluate quality of life in patients with primary sclerosing cholangitis (PSC) as a means to better understand the global experience faced by patients with this disease.

  Although many patients with PSC in time will go on to need liver transplantation for liver failure related complications, reductions in quality of life are important on an individual basis. The slow natural history of the disease means that quality of life concerns can have significant impact on patients and their families over many years. Symptom evaluation is often poorly performed in routine clinic practice and frequently underestimated by clinicians. Abdominal pain, fatigue, itch, and anxiety are commonly voiced by patients with PSC. This reflects both the nature of a chronic cholestatic liver disease, but also the significant uncertainty associated with a diagnosis of PSC. No disease specific tool exists to help patients and their clinicians quantify symptoms and measure quality of life for these patients in a reproducible, objective fashion. Furthermore no tool is available to aid in the development of new treatments for this disease, the efficacy of which should include evaluation of patient defined quality of life.

  Our proposal will evaluate patients with PSC both before and after liver transplant, in two clinic practices in Ontario, and identify symptoms and concerns that are relevant to patients. By correlation with clinical aspects of disease we hope to identify major factors of concern to patients, and use these to ultimately develop a disease specific quality of life tool.

Grants Awarded Through American Association for the Study of Liver Diseases (AASLD)

PSC Partners Seeking a Cure awards a $3,000 prize annually at the annual meeting of the American Association for the Study of Liver Diseases (AASLD) award for the most promising research in PSC given at the fall American Association for the Study of Liver Diseases meeting.

2009 Award
Dr. V.S. Teaberry was the recipient of the PSC Partners-funded award. Her study is entitled: Novel Role for Hedgehog Pathway Activation in the Pathogenesis of Primary Sclerosing Cholangitis. Authors are: V.S. Teaberry; G.F.Karaca; R.P. Witek; W. Syn; A. Omenetti; Y. Jung; S.S. Choi; A. Diehl.

2008 Award
The recipients of the 2008 PSC Partners Seeking a Cure AASLD Awards were Dr. I. Tornai (2nd Department of Medicine, University of Debrecen, Debrecen, Hungary), and Dr. P. G. Blanco (Beth Israel Deaconess Medical Center, Boston, MA, USA), as described in the AASLD 2008 Annual Report and in The Duct newsletter on pages 24 and 25, at this site:

• http://www.pscpartners.org/DuctSummer09part2.pdf

2007 Award
The recipient of the 2007 PSC Partners Seeking a Cure AASLD Award was Dr. Thomas H. Karlsen (Medical Department and Institute of Immunology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway), as described in the AASLD 2007 Annual Report and in The Duct on pages 8-9 at this site:

• http://www.pscpartners.org/NewsVol-3-2.pdf

Grants Awarded to Specific Research Projects

STOPSC
PSC Partners has awarded $40,000 to the Studies of Primary Sclerosing Cholangitis research project, a multi-center effort (in Canada and the US) to better understand the disease, develop better ways to detect it, find out how effective current treatment may be, and conduct research on aspects of the disease.