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. 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 $530,706 in PSC research. Grant awards are made on an annual basis.

Awarded in 2010

PSC Partners Seeking a Cure received 13 grant proposals in August 2010, and these were reviewed and ranked by the Scientific/Medical Advisory committee. Five proposals were selected for two years of funding in this competition:

* Pathogenesis of PSC: Role of TGR5 in the regulation of the innate immune response in the biliary epithelium. Mario Strazzabosco, M.D., Ph.D, Department of Internal Medicine Section of Digestive Diseases, Yale University, 333 Cedar Street-1080 LMP, P.O. Box 208019, New Haven, CT 06520-8019, and Michael Trauner, M.D., Ph.D, Department of Internal Medicine III, Divison of Gastroenterology and Hepatology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Amount awarded = $40,000 over years.

* Epigenetics associated with primary sclerosing cholangitis in monozygotic twins discordant for the disease. Carlo Selmi, MD, PhD, Assistant Professor of Internal Medicine, University of Milan, Physician Scientist, IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Assistant Professor of Medicine, University of California, Davis, Division of Rheumatology, Allergy, and Clinical Immunology, GBSF suite 6515, 451 E Healthy Sciences Drive, Davis, CA 95616. Amount awarded = $40,000 over 2 years.

* Identification of genetic profiles unique to PSC-IBD. Judy Cho, M.D., Associate Professor of Medicine and Genetics, Section of Digestive Diseases, Director, Inflammatory Bowel Disease Center, Yale University, Internal Medicine, 333 Cedar Street, Room LMP-1072, P.O. Box 208056, New Haven, CT 06520-8056. Amount awarded = $40,000 over 2 years.

* Combination treatment with ursodeoxycholic acid and all-trans retinoic acid for primary sclerosing cholangitis (PSC). Shi-Ying Cai, Ph.D., Research Scientist, Section of Digestive Diseases, Department of Internal Medicine, Yale Liver Center, Yale University School of Medicine, 1080 LMP, 333 Cedar Street, New Haven, CT 06520, and James L. Boyer, M.D., Ensign Professor of Medicine, Section of Digestive Diseases, Department of Internal Medicine, Yale Liver Center, Yale University School of Medicine, 1080 LMP, 333 Cedar Street, New Haven, CT 06520. $37,000 over 2 years.

* Establishing the role and molecular mechanisms for pregnane X receptor in progressive sclerosing cholangitis. Sridhar Mani, M.D., Professor, Medicine, Oncology and Genetics, Miriam Mandel Faculty Scholar in Cancer Research, Albert Einstein College of Medicine, 1300 Morris Park Ave, Chanin 302D-1, Bronx, NY 10461. $40,000 over 2 years.

Central themes of the research projects funded in this round, are: genetics and "epigenetics" of PSC, and the use of mouse models of sclerosing cholangitis to probe the pathogenesis mechanisms and accelerate development of novel therapies.

The following are the Project Summary and Specific Aims sections of the funded proposals. Each Project Summary/Specific Aims description of the project (provided by the investigators) is followed by a brief "Interpretation for the layperson" (prepared by David Rhodes). David Rhodes accepts full responsibility for any errors/omissions that may occur in these "layperson" interpretations. 

Pathogenesis of PSC: Role of TGR5 in the regulation of the innate immune response in the biliary epithelium.

Mario Strazzabosco, M.D., Ph.D, Department of Internal Medicine Section of Digestive Diseases, Yale University, 333 Cedar Street-1080 LMP, P.O. Box 208019, New Haven, CT 06520-8019, and Michael Trauner, M.D., Ph.D, Department of Internal Medicine III, Divison of Gastroenterology and Hepatology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Amount awarded = $40,000 over 2 years.

Summary

The etiology and pathophysiology of PSC remain unclear. The strong association with IBD suggests a dysregulation of the innate immunity system and among the different hypothesis, an increased response to bacterial products released by a ”leaky gut” has been suggested. This hypothesis has not been adequately tested because of the lack of adequate animal models. PSC has several features in common with Cystic Fibrosis, an autosomic recessive disease caused by mutation in CFTR, a cAMP-stimulated chloride channel that is involved in the secretory function of the biliary epithelium. We have recently found that CFTR deficiency alters the innate immunity of the biliary epithelium and generates a strong TLR4-mediated inflammatory response when the epithelium is exposed to endotoxins. Recent data suggest that TGR5, a Gprotein-coupled receptor for bile acids, that increases cellular cAMP, co-localizes with CFTR and regulates CFTR targeting and function in response to bile acids. The recent finding that the TGR5 gene is a likely disease gene in PSC let us to hypothesize that, similarly to CFTR, TGR5 may be a regulator of TLR4-mediated innate immunity and that a defective function of TGR5 may lead to an excessive inflammatory response to LPS. In this project, we plan to study the liver inflammatory response to DSS-colitis in TGR5-knockout mice, the effects of LPS on cytokine secretion in cultured TGR5-KO cholangiocytes, and the role of TGR5 on the regulation of the TLR4 pathway. These studies will eventually provide a strong rationale for the development of new therapies.

Specific Aims

Sclerosing cholangitis is a spectrum of progressive cholestatic liver diseases characterized by obliterative fibrosis and inflammation of the intrahepatic and/or extrahepatic biliary system. Primary Sclerosing Cholangitis (PSC) is associated with inflammatory Bowel Diseases (IBD), but while IBD is present in 75-80% of PSC cases, only 5-8 % of patients with IBD develop PSC. The etiology and pathophysiology of PSC, as well as the nature of the relationship with IBD remain unclear. Besides the “autoimmune” and the “toxic bile” hypothesis, the “leaky gut” hypothesis suggests that PSC is caused, in susceptible individuals, by exposure of the biliary tree to bacterial endotoxins. The lack of experimental models has hampered progresses in the study of PSC pathogenesis. Recent data generated by our lab indicate that cystic fibrosis may represent an interesting model disease. Cystic Fibrosis (CF) is a genetic disorder of secretory epithelia, caused by the defective function of a Cl- channel essential for bile secretion, called CFTR.. Several patients with CF present a cholangiopathy that shares many similarities with PSC. Both conditions manifest as a slowly progressive fibrosing cholangitis, affecting any tract of the biliary tree, with similar histologic and radiographic findings and a common evolution in biliary cirrhosis. Similar to PSC, that affects only a minority of IBD patients, liver disease affects a minority of CF patients. CFTR-knockout (CTR-KO) mice do not show spontaneous liver pathology, but develop a severe cholangitis after induction of colitis with dextran sodium sulfate (DSS). DSS-treatment had no effects on wildtype animals, suggesting that development of biliary inflammation and liver disease required the interaction between genetic predisposition and acquired factors. We have shown that, independently from the secretory defect, the biliary tree of CF-KO mice is more susceptible to endotoxins that enter the portal circulation because of the increased intestinal permeability. In fact, CFTR-defective cholangiocytes show an altered posttranslational regulation of TLR4 activity, and exhibit a stronger Src-dependent TLR4/NF-kB-mediated inflammatory response to an endotoxin challenge. Thus, CF-cholangiopathy, rather than being the consequence of ductal cholestasis, results from altered innate immune responses of CFTR-KO cholangiocytes. Similar mechanisms may apply to the primary form of sclerosing cholangitis. Recent genome wide association data provided circumstantial evidence that the G-protein-coupled bile acid receptor-1 (gpr1 or TGR5), is a potential disease gene in PSC. TGR5 is a bile acid receptor that generates cAMP upon binding of bile acids. TGR5 was shown to colocalize with CFTR and to be able to activate and stimulate the translocation of CFTR to the apical membrane of gallbladder cells. Moreover, TGR5 was shown to mediate bile-acid-induced suppression of LPS-induced cytokine secretion in macrophages. Thus, we hypothesize that, similar to the mechanism we have shown for CFTR, TGR5 modulates the innate immune response in cholangiocytes, and that defective function of TGR5 my lead to an excessive inflammatory response to LPS.

The hypothesis will be addressed through the following specific aims:

Aim 1: to study the effects of DSS-induced colitis on biliary inflammation in TGR5-KO mice.
Aim 2: to study the effects of LPS on cytokine secretion in cultured TGR5-KO and WT cholangiocytes.
Aim 3: to study the role of TGR5 on TLR4 pathway regulation in cultured TGR5-KO and WT cholangiocytes.

These studies will generate a better understanding of the innate immune response mechanisms in cholangiocytes and of the pathogenesis of PSC. Furthermore, the results of our study are likely to have a strong translational potential because several therapeutic molecules able to target these mechanisms are being developed.

Interpretation for the Layperson

One of the explanations for the cause of PSC (primary sclerosing cholangitis) in association with inflammatory bowel disease (IBD) is that an immune dysregulation in the gut leads to a "leaky gut" which allows toxic bacterial products to be transported to the liver, causing inflammation around the bile ducts. Both genetic and environmental factors may be involved in disease development and progression. It is essential that we understand the precise causes of PSC, so that we can ultimately learn how to slow or halt disease progression. Significant progress has been made in recent years concerning the identification of genes that may be associated with PSC. An important research approach is to take information obtained from these human PSC genetic studies to develop mouse models that mimic human PSC. Such models will be critical in understanding the pathogenic mechanisms, and accelerating the development of novel therapies. One of the exisiting mouse models of PSC is the cystic fibrosis mouse model. When given colitis, the cystic fibrosis transmembrane conductance regulator (CFTR) deficient mouse develops bile duct injury closely resembling human PSC. The CFTR gene encodes a protein that functions in bicarbonate secretion into bile. This mouse model has already been used to show that docosahexaenoic acid (DHA; a component of fish oil) protects against bile duct injury, and has led to clinical trials of DHA in the treatment of PSC. The relevance of this mouse model to human PSC is that variants of the cystic fibrosis gene have been associated with PSC, and pediatric PSC patients have been shown to have a dysfunction of the cystic fibrosis protein.

The TGR5 gene has been recently identified as a strong candidate for a susceptibility gene in PSC by the Norwegian PSC research center. The TGR5 gene encodes a protein that is a "bile acid sensor" and a regulator of the cystic fibrosis protein. To learn more about what TGR5 is doing, the researchers will use mice in which TGR5 has been knocked-out, and study whether the mice develop sclerosing cholangitis. Drs. Strazzabosco and Trauner will test whether deleting the TGR5 gene in mice will result in an abnormal inflammatory response to the bacterial product lipopolysaccharide (LPS; also known as endotoxin). A characteristic feature of inflammation caused by endotoxin is the activation of the pro-inflammatory complex, nuclear factor kappa-B (NF-kB). Endotoxin binds to the Toll-like receptor 4 (TLR4) and activates NF-kB. Thus, the assessment of the effect of deletion of TGR5 on TLR4-NF-kB pathway regulation in biliary cells (cholangiocytes) will provide important information about the inflammatory mechanisms controlled by TGR5. Drugs that target TGR5 are already in development, and so this study will pave the way for testing whether these drugs may inhibit liver inflammation. Drs. Strazzabosco and Trauner have extensive experience working with mouse models of sclerosing cholangitis, and have been instrumental, respectively, in clarifying the disease mechanisms in biliary tract diseases, and in demonstrating that nor-ursodeoxycholic acid (nor-UDCA) is superior to ursodeoxycholic acid (UDCA) in preventing liver injury, and bringing nor-UDCA to human clinical trials.

The first year of this project will be funded by a generous donation from Craig and Ali Wiele.

Epigenetics associated with primary sclerosing cholangitis in monozygotic twins discordant for the disease.

Carlo Selmi, MD, PhD, Assistant Professor of Internal Medicine, University of Milan, Physician Scientist, IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Assistant Professor of Medicine, University of California, Davis, Division of Rheumatology, Allergy, and Clinical Immunology, GBSF suite 6515, 451 E Healthy Sciences Drive, Davis, CA 95616. Amount awarded = $40,000 over 2 years.

Summary

Primary sclerosing cholangitis (PSC) is characterized by the presence of a chronic and relapsing inflammation of the biliary tract. As illustrated by recent association studies, genomic factors cause individual susceptibility in a subgroup of patients. Monozygotic (MZ) twins are a powerful tool to estimate the role of genetic and environmental factors, yet the concordance rate for PSC in such twins is unknown. Epigenetic changes are ideal candidates to provide a link between genomic susceptibility and environmental stimuli, particularly in the unique model of MZ twins discordant for the disease. We will take advantage of MZ twins discordant for PSC to utilize cutting-edge technologies which allow a large-scale analysis of epigenomics to address two specific issues:

Issue #1. Do MZ twins discordant for PSC manifest consistent patterns in terms of DNA methylation changes within repetitive and non-repetitive elements? We will utilize custom-designed MeDIP multiplex arrays for non repetitive and the most represented repetitive elements (LINE-1, Alu). Issue #2. Does the expression of candidate genes identified through the previous aim differ between discordant MZ twins? We will utilize RTPCR on mRNA samples and then pinpoint methylation differences through bisulfite sequencing. Issue #3. Is there an in silica disease model that can be summoned from the identified putative genes? The results obtained are expected to provide insights into putative epigenetic marks implicated in PSC onset that may well be integrated with the recently identified genetic loci. These results ultimately provide the bases for new epigenetic treatments in inflammatory conditions.

Specific Aims

We will take advantage of samples already available to the proponent from 6 MZ twin pairs discordant for PSC. Samples include DNA, mRNA, and mononuclear cells from peripheral blood and were previously obtained by the proponent through a worldwide effort supported by PSC Partners Seeking a Cure. We will take advantage of this unique cohort and of cutting-edge molecular methods to address two complementary and one ultimate issue.

Issue #1. Do MZ twins discordant for PSC manifest consistent patterns in terms of DNA methylation changes within repetitive and non-repetitive elements? Issue #2. Does the expression of candidate genes identified through the previous aim differ between discordant MZ twins? What is the methylation pattern of single CpG sites within differently expressed genes? Issue #3. Is there an in silica disease model that can be summoned from the identified putative genes? This analytical step will include data from the recently concluded genome-wide genetic association study as well as from the present proposal. Such findings will be utilized with the appropriate bioinformatics tools to determine what molecular pathways are involved in PSC pathogenesis or whether a genetic signature can be extrapolated.

Interpretation for the Layperson

It is estimated that first-degree relatives of PSC patients have a 40-fold higher risk of developing PSC than the general population. Therefore there is a strong genetic component to PSC. The genetic basis of PSC is likely to be complex involving more than one gene and may well be insufficient to explain disease onset. There may also be as yet unknown environmental factors contributing to disease initiation and progression. At the interface between genetics and environment is a relatively new field of research called "epigenetics". Here, certain gene modifications can take place, such as methylation of cytosine residues of DNA, converting cytosine to 5-methylcytosine, mostly at sites called "CpG sites". When some areas of the genome are methylated more heavily than others this can alter gene expression and thus the production of the corresponding protein. A key approach to discovering whether epigenetic changes are involved in disease development/progression is to carefully examine the DNA methylation patterns of monozygotic twins (i.e. twins that are genetically identical) but differ with respect to disease (i.e. only one twin is affected, and the pair is thus discordant for disease). This approach has been used by Dr. Selmi and colleagues to investigate the role of "epigenetics" and DNA methylation in particular, in primary biliary cirrhosis (PBC), a liver disease that mostly affects women. These pioneering studies have recently shown that monozygotic twins that are discordant for PBC have distinct methylation patterns of certain genes on the X chromosome. Dr. Selmi and colleagues will now extend these studies to investigate DNA methylation patterns in 6 pairs of monozygotic twins discordant for PSC, recruited with the assistance of PSC Partners Seeking a Cure. The results of this project are expected to provide insights into putative epigenetic markers implicated in PSC onset, painting a more complete picture of the genetic landscape of PSC and its interface with environmental exposures. These results may ultimately provide the basis for novel epigenetic treatments.

Identification of genetic profiles unique to PSC-IBD.

Judy Cho, M.D., Associate Professor of Medicine and Genetics, Section of Digestive Diseases, Director, Inflammatory Bowel Disease Center, Yale University, Internal Medicine, 333 Cedar Street, Room LMP-1072, P.O. Box 208056, New Haven, CT 06520-8056. Amount awarded = $40,000 over 2 years.

Project Summary

The primary goal of this proposal is to better understand the relationship between the primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD). We propose to accomplish this by identifying the genetic and genomic factors which contribute to the cause of PSC-IBD, and comparing this to identified genetic and genomic factors associated with Crohn’s disease (CD) and ulcerative colitis (UC). Identification of these factors will ultimately contribute to better screening for disease risk, improve predictions of disease severity, influence treatment regimens and advance therapies for treatment and quality of life care. PSC-IBD is poorly characterized, clinically and genetically. A strong association has been observed with IBD and PSC, some analyses identified IBD in 80-90% of PSC patients. Conversely, about 5% of UC patients will have associated PSC compared to 3.4% of CD patients. Genetic contributions to both have been confirmed epidemiologic studies and by the identification of genetic associations for both IBD and PSC. A recent GWAS found the strongest PSC association for the HLA-B region at chromosome 6p21, and some evidence for associations at 2q35, 3p21 and 13q31. Interestingly, significant associations were not found for confirmed UC susceptibility loci. These observations underlie PSC and IBD as complex genetic traits, and support the hypothesis that PSC-UC is a distinct sub-phenotype of IBD. We plan to advance the genetic and genomic knowledge in PSC-IBD by expanding the collection of PSC-IBD cases and biospecimen collections (Specific Aim #1). We propose to compare and contrast both the genetic loci (Specific Aim #2) and peripheral blood serum miRNA patterns (Specific Aim #3) between PSC and IBD. The unique relationship between PSC and IBD provides an ideal opportunity to leverage these comparative studies to provide insight into disease mechanisms and course.

Specific Aims

Specific Aim #1: Development and expansion of PSC-IBD resources for collaborative genetic and genomic studies. We propose to recruit patients and collect phenotype data and biospecimens from individuals with PSC-IBD using uniform protocols to enhance collaborative studies. Identification and a better understanding of the genetic factors contributing to PSC-IBD will greatly increase the potential for identifying disease predictors/markers, novel therapies for disease management and/or the prevention of invasive treatments.

Specific Aim #2: To compare and contrast genetic loci between PSC and IBD. The Immunochip Consortium has developed a genotyping platform which includes all inflammatory disease loci, many of which are shared between different diseases. We propose studies to define the genetic overlap between PSC and IBD, with a particular focus on combining PSC data with two IBD subtypes, namely,extensive colitis and fibrostenosing CD.

Specific Aim #3: To compare and contrast peripheral blood serum miRNA patterns between PSC and IBD. We propose a pilot study to explore the feasibility of using micro-RNAs as biomarkers for PSC-IBD. The analysis of miRNAs in peripheral blood may provide an important and novel source for biomarkers. At present the extent to which small RNAs can be specifically mapped to and regulate, protein-coding mRNA expression is unknown. However, given the plethora of SNP associations in 3’UTR regions, specifically for IBD, the concept that disease-associated variation may modulate mRNA expression through variable miRNA regulation of genetic variation will be explored. We propose an initial analysis of circulating miRNA from serum of CD, UC, PSC-IBD cases and healthy controls.

Interpretation for the Layperson

PSC (primary sclerosing cholangitis) is strongly associated with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC). Both genetic and environmental (possible also dietary) factors may be involved in disease development and progression. Much work during the last decade by the NIDDK Inflammatory Bowel Disease Genetics Consortium (led by Dr. Judy Cho [http://medicine.yale.edu/intmed/ibdgc/]) has identified a multitude of genes associated with UC and Crohn's disease. The identification of these genes is leading to a more complete understanding of the mechanisms of UC and Crohn's disease initiation and progression, and identification of new targets for intervention, and novel therapies for disease management. Parallel studies on the genetics of PSC are beginning to reveal that the IBD associated with PSC may have a different genetic signature from classic UC and Crohn's disease. Dr. Judy Cho will rigorously investigate this important question by recruiting patients and collecting phenotype data and biospecimens from individuals with PSC-IBD for comparison with classic UC and Crohn's disease patients, and healthy controls. Dr. Cho will use the "Immunochip" [which includes all known inflammatory disease genes] to investigate the precise genetic overlap between PSC and the various forms of IBD.

There is recent interest in whether microRNAs (small RNA molecules with potent gene regulatory functions) play a role in IBD and PSC [Dr. Invernizzi at UC Davis is currently funded by PSC Partners Seeking a Cure to investigate whether specific microRNAs are associated with PSC and cholangiocarcinoma]. Dr. Cho will extend this work to determine if circulating microRNAs in the serum of Crohn's disease, UC, and PSC-IBD patients differ from one another, and from healthy controls. This work may lead to new diagnostic tools, perhaps enabling early identification of UC and Crohn's disease patients who may be at risk for developing PSC.

This project will be entirely funded by our anonymous donor who generously donated $100,000 in our Itching for a Cure: Road to Connecticut fundraiser of 2009/2010 to help support PSC research.

Combination treatment with ursodeoxycholic acid and all-trans retinoic acid for primary sclerosing cholangitis (PSC).

Shi-Ying Cai, Ph.D., Research Scientist, Section of Digestive Diseases, Department of Internal Medicine, Yale Liver Center, Yale University School of Medicine, 1080 LMP, 333 Cedar Street, New Haven, CT 06520, and James L. Boyer, M.D., Ensign Professor of Medicine, Section of Digestive Diseases, Department of Internal Medicine, Yale Liver Center, Yale University School of Medicine, 1080 LMP, 333 Cedar Street, New Haven, CT 06520. Amount awarded = $37,000 over 2 years.

Project Summary

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease of the liver and bile ducts that generally leads to progressive liver failure. The pathogenesis of PSC remains enigmatic, but malfunction of hepatic immunity has been proposed to play a role in the development/progression of the disease. There is no FDA approved medical treatment for PSC. Although norUDCA has shown beneficial effects in Mdr2 (Abcb4) knockout mice (an animal model for PSC), there is an urgent need to develop novel treatment strategies and to test them in animal models and in PSC patients. Very recently, we have found that combination treatment with UDCA and retinoic acid substantially improved animal growth rate and significantly reduced bile salt pool size, liver fibrosis, necrosis, inflammation, and bile duct proliferation in an animal model of cholestasis, the common bile duct ligated rat. (UDCA and retinoic acid are FDA-approved medications for treating primary biliary cirrhosis and acute promyelocytic leukemia and inflammatory disorders such as psoriasis, acne, and rheumatoid arthritis, respectively). Parts of the molecular mechanisms of this beneficial effect of UDCA and retinoic acid have also been verified in primary human liver cells, including hepatocytes and hepatic stellate cells (manuscript submitted for publication). Therefore, we propose to test if RA alone or in combination with UDCA will improve liver pathology in Mdr2-/- mice. Completion of the proposed study will provide critical information for determining whether RA alone or in combination with UDCA might be potentially beneficial for patients with PSC. If this project demonstrates beneficial effects in this animal model, we plan to test this therapy in patients with PSC.

Specific Aims

The specific aim of this study is to determine whether RA alone or in combination with UDCA has beneficial effects on liver fibrosis, necrosis and or inflammation in Mdr2-/- mice, an animal model for PSC.

Interpretation for the Layperson

It is urgent that novel therapies/treatment strategies be developed for PSC, and the use of mouse models of sclerosing cholangitis will be critical in accelerating the discovery and pre-clinical testing of these new approaches. It is well recognized that vitamin A deficiencies are common in PSC patients, and that the deficiencies become more pronounced as the disease progresses. The liver is a major storage organ for vitamin A, and as cholestatic liver diseases progress, this vitamin A can be released from the vitamin A storing cells of the liver (hepatic stellate cells) as they transition away from vitamin A storage towards a state that promotes collagen biosynthesis and liver fibrosis. Vitamin A (retinol) is a precursor of all-trans retinoic acid (RA), and so loss of vitamin A during advancing liver disease may lead to retinoic acid deficiencies, which may in turn contribute to a vicious cycle of inflammation, necrosis and fibrosis. In this proposal, Drs. Cai and Boyer will test whether the combination of ursodeoxycholic acid (UDCA) with retinoic acid (RA) will be superior to the individual drugs alone in delaying liver fibrosis, necrosis and inflammation in a mouse model of sclerosing cholangitis, the Mdr2 (-/-) mouse model. Should positive results be obtained in these studies, this combination therapy can be immediately tested in patients with PSC.

This project will be entirely funded by our anonymous donor who generously donated $100,000 in our Itching for a Cure: Road to Connecticut fundraiser of 2009/2010 to help support PSC research.

Establishing the role and molecular mechanisms for pregnane X receptor in progressive sclerosing cholangitis. Sridhar Mani, M.D., Professor, Medicine, Oncology and Genetics, Miriam Mandel Faculty Scholar in Cancer Research, Albert Einstein College of Medicine, 1300 Morris Park Ave, Chanin 302D-1, Bronx, NY 10461. $40,000 over 2 years.

Project Summary

We and others have demonstrated that orphan nuclear receptors like pregnane x receptor (PXR) abrogates intestinal inflammation induced by xenobiotic compounds (e.g., DSS). These experiments serve as a proof-of-concept that PXR plays a significant role in pathogenic diseases of the gut that result from unregulated inflammatory responses (e.g., IBD). Fish oils have beneficial effects on inflammation and are relatively non-toxic xenobiotics. Since the pathogenesis of progressive sclerosing cholangitis is parallel to that observed in arteriosclerotic inflammation (where fish oils show clear benefit), our 2-year project will focus on determining the significance of PXR activation in the pathogenesis and maintenance of PSC. Specifically, we will use the DDC-induced mouse model of cholangiopathy in our mouse models of PXR activation [PXR wt type, PXR-/- and humanized (h)PXR] to determine if PXR activation by non-hepatotoxic agonists (e.g., hyperforin or rifampicin) abrogates biliary inflammation. In our second aim, we will determine whether PXR mediates the actions of fish oils in abrogating biliary inflammation. Specifically, we hypothesize that fish oils will transactivate PXR and inhibit inflammation.

Specific Aims

1. To determine the effect of PXR activation on biliary inflammation in the DDC-induced mouse model of cholangiopathy in PXR+/+, PXR-/- and humanized PXR mice. DDC induces a cholangiopathy in mice at 8 weeks of treatment that resembles early inflammatory changes seen in PSC. (a) To determine the effect of PXR on early inflammation in the bile duct tract, PXR +/+ will be treated with DDC (+ PCN, a potent mPXR agonist). At 4, 6 and 8 weeks, cohorts of mice from each genotype, will undergo histopathologic and immunohistochemistry assessment of the entire bile duct tract (intra- and extrahepatic) as previously described. (b) The same experiments will be repeated with PXR-/- and hPXR mice (+ hyperforin or rifampicin, potent hPXR agonists), with accurate sample size estimates obtained from data from (a). These experiments will determine the clinical impact of PXR in biliary inflammation as typified in PSC.

2. To determine the therapeutic efficacy of fish oils alone or in combination with classical PXR ligands on DDC-induced mouse models of cholangiopathy. Fish oils (DHA, EPA) are commercially available and serve as weak ligands to several nuclear receptors - RXRalpha and PPARalpha. Since PXR dimerizes with RXRalpha and is a direct target gene of PPARalpha, we hypothesize that fish oils will transactivate PXR and inhibit inflammation. Furthermore, we surmise that multiple ligands acting on PXR, given its promiscuous ligand-binding pocket, will synergistically activate PXR and inhibit inflammation. To test this concept, we will treat PXR+/+, PXR-/- and humanized PXR mice with vehicle, fish oils and/or PCN (as mPXR ligand) or rifampicin (as hPXR ligand).

Interpretation for the Layperson:

It is becoming clear that there is a complex network of nuclear receptors in the gut and liver that are "master" controllers of gene expression, regulating all aspects of metabolism, ranging from bile acid transport and detoxification, to energy metabolism, to lipid metabolism, and circadian rhythms (day-night cycles). An important "master" contoller is the receptor called pregnane X receptor (PXR), also known as the steroid and xenobiotic receptor (SXR). PXR is known to be down-regulated in ulcerative colitis, and the PXR gene itself may be an ulcerative colitis susceptibility gene, and a gene that affects the rate of progression of PSC. This receptor plays an important role in detoxification of lithocholic acid, a toxic bile acid produced from ursodeoxycholic acid (UDCA) by gut bacteria. Recent studies indicate that activation of PXR by drugs such as rifampin (rifampicin) and rifaximin results in reduction of inflammation and fibrosis.

Because the adverse effects of high-dose UDCA in PSC may be associated with conversion of UDCA to lithocholic acid, there is also particular urgency in investigating whether drugs that target PXR may help prevent these adverse effects of UDCA.

In this proposal, Dr. Mani will use humanized mice in which the mouse PXR gene has been replaced with the human PXR gene so that it responds to rifampin (rifampicin), and will then test whether activation of PXR by rifampin will result in a reduction of biliary inflammation.

Another "master" controller of gene expression in the liver and gut is the receptor called retinoid X receptor (RXR), which partners with PXR (and many other nuclear receptors) to regulate metabolism. A known activator of RXR is a component of fish oil, docosahexaenoic acid (DHA). It is plausible that the combination of DHA and rifampin, as activators of both RXR and PXR, respectively, will be superior to either drug alone in reducing inflammation. Dr. Mani will test this hypothesis. If positive results are obtained, this may lead to novel therapies in PSC, perhaps combining UDCA with rifampin and DHA. It should be noted that rifampin is already used by many PSC patients for the control of pruritus, and that DHA has shown some early positive results in reducing alkaline phosphatase levels in PSC patients. Some mouse models suggest that DHA may be protective against colitis and colorectal cancer, and there is growing evidence that human ulcerative colitis may be associated with low intake of omega-3 fatty acids such as those found in fish oils.

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.

  This project will be entirely funded by a generous donation from David and Ros 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.

2011 Award
Dr. B.D. Juran, of Mayo Clinic/Rochester, for Exome sequencing in a PSC family identifies a nonsense mutation in the biliary transporter ABCB4. Co-authors were: B.S. Petersen; J.R. Hov; A. Franke; T.H. Karlsen; and K. Lazaridis.

2010 Award
J. Eaton; M. G. Silveira; K. and D. Lindor, of the Mayo Clinic/Rochester, received the PSC Partners-funded award for High Dose Ursodeoxycholic Acid is Associated with the Development of Colorectal Neoplasia in Patients with Ulcerative Colitis and Primary Sclerosing Cholangitis

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.