The Lankenau Institute for Medical Research
Association: Resident Faculty
Dr. James Mullin’s research group bridges LIMR and the Division of Gastroenterology of Lankenau Medical Center. The group focuses on the connections (tight junctions) between the epithelial cells that make up the lining of the digestive tract, and how they become leaky in the early stage of gastrointestinal (GI) cancer and in inflammatory bowel diseases such as Crohn's Disease and Ulcerative Colitis. In association with clinicians at Lankenau Medical Center, Dr. Mullin's work is establishing the importance of GI leakiness in cancer and inflammatory. One example of where the Mullin group has found GI leakiness to be important is in Barrett's esophagus. Barrett's esophagus affects about 1-2% of adults in the US and occurs in individuals with chronic heartburn known medically as gastroesophageal reflux disease (GERD). It is too often a precursor to cancer of the esophagus which has a very high fatality rate. In a current patient-based study, Dr. Mullin’s group is determining if orally administered zinc can reduce the risk of cancer developing out of Barrett’s esophagus.
In a second project, Dr. Mullin is examining whether certain micronutrients (flavonoids, trace metals, bacterial metabolites) can reduce tight junctional leak and therefore have therapeutic application in treating Crohn’s Disease and/or Ulcerative Colitis. The Mullin group utilizes both cell culture studies and patient-based studies in this overall project.
Research in our group focuses on the breakdown of the epithelial barrier lining of the major organs of the GI tract in various disease states and as a result of various types of inflammatory proteins and chemicals in general. We are particularly interested in the regulation of the tight junction, a gasket-like seal, which limits transit across the epithelium through the paracellular or “between cell” pathway. We have shown that phorbol esters, which are known tumor promoting chemicals, activate the signaling protein, PKC, in our renal and gastrointestinal epithelial cell culture models and increase tight junctional leak. We documented a similar phenomenon occurring with proinflammatory cytokines and with certain oncogene mutations. We have observed that specific tight junction proteins, such as occludin and various claudins, are targeted. The leak of tight junctions in precancerous epithelial tissues may allow growth factors like EGF to enter sub epithelial tissue and enhance tumor development tumor microenvironments. Parallel studies from our group have demonstrated that the tight junctions between epithelia of normal human colon mucosa act as good barriers whereas the junctions between the epithelia of adenocarcinomas are all “leaky” Such leakiness may associate with aberrant colon crypts as well. The tight junction proteins of metaplastic epithelium of Barrett's esophagus also have this leaky character. Similar leak occurs in GI inflammatory diseases. A major emphasis in our group is to reduce such leak through increased exposure to certain key micronutrients that act to remodel the tight junction. The trace metal, zinc, the bioflavonoid, quercetin, and the commensal bacterial metabolites, indole and butyrate, are all active in this regard, and offer exciting new therapeutic possibilities. .
Inflammatory bowel disease associated with increased colon cancer risk has been linked with increased tight junction permeability as well as increased levels of proinflammatory cytokines, among them TNF. One biological significance of these findings is that if tight junctions become “leaky” in the course of tumor promotion or inflammation, growth factors normally restricted to the GI lumen may cross the epithelial barrier, access their receptors and stimulate cell growth and motility The leak itself may also be the cause of persistent inflammation in the tissue, by allowing bacterial antigens to move out of the GI lumen.
In addition to determining the pathophysiological conditions and mechanisms by which junctional seals (and epithelial barriers) become leaky, our group thus focuses also on how junctional seals can be strengthened – rendered less leaky – by nutritional means. The dietary interventions of caloric restriction and methionine restriction (both known to lengthen lifespan) as well as certain micronutrients may be achieving their benefits in part by inducing tighter junctional seals. Our group is currently investigating the mechanism of this effect, the characteristics of the reduced leak, and the implications it may have for reduced risk of cancer and inflammation in the enhanced tissue.
Due to the favorable environment at Lankenau, with its close interplay between basic research and clinical medicine, the above research programs are pursued using cell culture and animal models, but also small patient-based, clinical trials performed jointly with the Division of Gastroenterology of Lankenau Medical Center.
Dr. Mullin's Google Scholar page