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School of Medicine
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Ongoing Research in Gastroenterology and Hepatology
Researchers examine every facet of the digestive system to find better ways to treat illnesses and conditions that originate in the gastrointestinal system, liver and pancreas.
The goal of the lab's research is to identify molecular abnormalities that can improve the outcome of patients with pancreatic cancer and those at risk of developing this disease. Much of our work is focused on translational research evaluating markers and marker technologies that can help screen patients with an increased risk of developing pancreatic cancer.
Thus, marker efforts have been focused mostly on identifying markers of advanced precancerous neoplasia (PanINs and IPMNs) that could improve our ability to effectively screen patients at risk of developing pancreatic cancer. We lead or participate in a number of clinical research protocols involved in the screening and early detection of pancreatic neoplasia including the CAPS clinical trials. We maintain a large repository of specimens from cases and controls with and without pancreatic disease and use this repository to investigate candidate markers of pancreatic cancer for their utility to predict pancreatic cancer risk.
In addition, we have been working to identify familial pancreatic cancer susceptibility genes and identified BRCA2 as a pancreatic cancer susceptibility gene in 1996. We participate in the PACGENE consortium and the familial pancreatic cancer sequencing initiative. My lab also investigates pancreatic cancer genetics, epigenetics, molecular pathology, tumor stromal interactions and functional analysis of candidate genes and miRNAs. Dr. Goggins is the principal investigator of a phase I/II clinical trial evaluating the Parp inhibitor, olaparib along with irinotecan and cisplatin for patients with pancreatic cancer. view more
A major focus in our laboratory is extracellular matrix (ECM), and its role in innate immune inflammatory responses at mucosal surfaces. The ECM has a significant role in modulating the local inflammatory milieu, while its breakdown can present immune cells with endogenous danger signals to drive excessive immune responses. However, these events are poorly understood.
Our studies on lumican, one such ECM protein, shows that its expression increases in Crohn’s disease and mouse models of colitis. We found that a segment of the lumican protein interacts with toll-like receptor 4 on neutrophils and macrophages that regulates innate immune response and production of inflammatory cytokines. We developed mice deficient in lumican that show poor recovery from a chemically induced colitis. The function of lumican in inflammation may be a double-edged sword—needed for development of protective innate immunity but unrestricted can cause immune dysregulation and chronic inflammation.
We are... currently investigating the molecular nature of lumican interactions with host immune functions and developing mimetic peptides and anti-lumican antibodies that could be ultimately used to modulate inflammation. Treatments using anti-TNF-? or other antibodies that block major components of the immune response may have harmful immunosuppressive effects.
Future treatment strategies based on lumican or other proteins of the ECM could become milder approaches to suppress localized inflammation. Recently, we have started investigating, biglycan another lumican-like ECM protein that is perceived as an endogenous danger signal in chronic inflammatory settings.
Our laboratory has examined differential gene expression patterns in Crohn’s disease and ulcerative colitis to establish signature expression patterns. A subset of these genes will be pursued in the future for elucidating pathogenesis of these two related inflammatory bowel diseases. view more
Dr. Meltzer is an internationally renowned leader in the molecular pathobiology of gastrointestinal malignancy and premalignancy. He invented molecular methods to detect loss of heterozygosity in tiny biopsies, triggering an avalanche of research on precancerous lesions. He was the first to comprehensively study coding region microsatellite instability, leading to the identification of several important tumor suppressor genes. He performed several groundbreaking genomic, epigenomic and bioinformatic studies of esophageal and colonic neoplasms, shifting the GI research paradigm toward genome-wide approaches. He directed an ambitious nationwide validation study of DNA methylation-based biomarkers for the prediction of neoplastic progression in Barrett’s esophagus.
Dr. Meltzer founded and led the Aerodigestive Cancer and Biomarker Interdisciplinary Programs at the University of Maryland, also becoming associate director for core sciences at that school’s Cancer Center. He currently hol...ds an endowed professorship and is the director of GI biomarker research at Johns Hopkins.
The laboratory group focuses its efforts on the molecular genetics of gastrointestinal cancers and premalignant lesions, as well as on translational research to improve early detection, prognostic evaluation, and treatment of these conditions. Below, some examples of this work are described. view more
Investigators in the IBD and Autoimmune Liver Diseases Laboratory conduct basic and translational research in inflammatory bowel disease (IBD) and autoimmune liver diseases. One area of focus is discovering and developing biomarkers for diagnosing and prognosticating IBD and other autoimmune liver diseases (AILDs). We also are exploring the molecular pathogenesis of—and developing novel therapies for—IBD. In addition, we are working to understand the molecular reason why many IBD patients fail to respond to mainstay drug therapies—and to develop diagnostic assays that can predict non-responders before starting them on those therapies. These biomarker studies have led to our application for four U.S. and international patents.
Risk Factors for Inflammatory Bowel Disease
This study aims to examine environmental risk factors for inflammatory bowel disease including Crohn's disease, ulcerative colitis and indeterminate colitis.
Hepatic Fibrosis and Cirrhosis
This study is examining the mechanisms of liver fibrosis with emphasis on the inhibitory effects of fat-soluble vitamins on fibrosis. The studies are performed in vitro with stellate cells and in vivo in experimental models of liver fibrosis.
Immune Mediated Liver Diseases
The primary aim of the study is to determine the efficacy of mitomycin C intrabiliary bolus on survival and the progression of PSC. Other aims of the study are to determine the durable effect of mitomycin on interval duration between procedures, the total number of procedures needed over a two-year period for the routine management of PSC and the change of serum biochemical markers.
Intestinal Chloride Secretion
Researchers are studying the role of calcium-activated Cl channels in intestinal chloride secretion and determining whether the recently identified transmembrane protein 16 family of proteins is also involved in intestinal chloride secretion with a goal of providing background information for the development of drugs to treat diarrhea, constipation and cystic fibrosis.
This study seeks to understand the regulatory mechanisms of Clc-5 and NHE3. Preliminary data indicate that Clc-5 may directly or indirectly regulate NHE3 trafficking.
Nutrition, Gut Bacteria and Fatty Liver Disease
This study is directed toward understanding how dietary factors modify gut bacteria and their implications in fatty liver disease.