James M. Mullin, PhD

Email:  MullinJ@mlhs.org Phone: 484.476.2703 Fax: 484.476.2205 Office: R229 Department: Faculty Association: Resident Faculty

Education: B.S., Biology, St. Joseph's College, Philadelphia, PA, 1976 Ph.D., Physiology, University of Pennsylvania, Philadelphia, PA, 1980 Postdoctoral Fellow, The Wistar Institute, Philadelphia, PA Postdoctoral Fellow, Department of Human Genetics, Yale University School of Medicine Current Appointments: 1986 to Present: Professor, Lankenau Institute for Medical Research 2002 to Present: Director of Research, Department of Medicine, Division of Gastroenterology, Lankenau Medical Center, Wynnewood, PA 2002 to Present: Adjunct Professor, Department of Biology, St. Joseph's University, Philadelphia, PA 2005 to Present: Professor, Kimmel Cancer Center, Thomas Jefferson University School of Medicine 2008 to Present, Fellow of the American Gastroenterological Association (AGAF) 2011 to Present: Editorial Board, The Journal of Gastroenterology and Hepatology Research 2011 to Present: Editorial Board, The Scientific World Journal 2012 to Present: Editorial Board, Gastrointestinal Cancer: Targets and Therapy Research Interests: Role of gastrointestinal (tight junctional) leakiness in cancer, inflammatory disease, and drug delivery Google Scholar page Lab Personnel: Mary Carmen Valenzano, Biomedical Research Assistant Xuexuan Wang, Postdoctoral Fellow Christopher Farrell, GI Fellow

Lay Description:

Dr. James Mullin uncovered that the connections (tight junctions) between the cells that make up the digestive tract 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, inflammatory diseases and drug delivery. 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% 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. Barrett's remains frequently unnoticed until cancer occurs, and Dr. Mullin is developing an inexpensive and simple test (based on leak across the Barrett's lining) to determine which GERD patients are most in need of upper endoscopy to detect the presence of Barrett's prior to the occurrence of cancer.

In a parallel project, Dr. Mullin is examining whether reducing the amount of the essential amino acid methionine helps the digestive tract to become less leaky at the cellular connections The findings of this work could improve GI barrier function in numerous patients and thereby alleviate GI inflammation in diseases such as Crohn's. Together with doctors at Lankenau Medical Center, Dr. Mullin is investigating whether a diet with reduced methionine can reduce pain and suffering in patients with Crohn's disease, known to involve compromised barrier function of the digestive tract.

Proton pump inhibitors (PPIs) such as  Nexium, Prilosec and Zegerid are the second most widely prescribed drug type in the country, with over 90 million Rxs per year. They are used for the treatment of chronic heartburn and associated disorders. In a very interesting finding Dr. Mullin observed that PPIs cause a leak in the stomach. In a third project, Dr. Mullin's laboratory is looking to exploit PPI-induced gastric leak as a safe, effective means of delivering certain drugs orally rather than by injection. Oral drug delivery is a great improvement over other methods as it is painless and can be done at home rather than in medical offices.

Scientific Description:

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 drugs and chemicals in general (1). 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 ers, activate the signaling protein, PKC, in our renal and gastrointestinal epithelial cell culture models and increase tight junctional permeability [2-4]. We documented a similar phenomenon occurring with proinflammatory cytokines and with certain oncogene mutations (5,6). We have observed that specific tight junction proteins, such as occludin and various claudins, are targeted [2]. The leak of tight junctions in precancerous epithelial tissues may allow growth factors like EGF to enter subepithelial tissue and enhance tumor development tumor microenvironments [7]. 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"" [8]. 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 [9, 10].  As an offshoot to our work with Barrett's esophagus, our group serendipitously made a pharmacological finding that proton pump inhibitor drugs cause a transepithelial, paracellular leak in the gastric epithelium (11).  Our group is currenbtly exploring the potential compklications of such leak, but also exploring the possibility of utilizing the leak for delivery of peptide and oligonucleotide drugs orally (12).

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. The 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. [1,7].

In addition to determining the pathophysiological conditions and mechanisms by which junctional seals (and epithelial barriers) become leaky, our group has also found that junctional seals can be strengthened – rendered less leaky – by nutritional means (13). The dietary interventions of caloric restriction and methionine restriction (both known to lengthen lifespan) 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 (10).

Dr. Mullin's Google Scholar page

Selected Publications:

1. Murray LJ, Gabello M, Rudolph DS, Farrell CP, Morgan M, Martin AP, Underwood JC, Valenzano MC, Mullin JM. Transmucosal gastric leak induced by proton pump inhibitors. Dig Dis Sci. 2009 Jul;54(7):1408-17. 
2. Mullin JM, Valenzano MC, Whitby M, Lurie D, Schmidt JD, Jain V, Tully O, Kearney K, Lazowick D, Mercogliano G, Thornton JJ. Esomeprazole induces upper gastrointestinal tract transmucosal permeability increase. Aliment Pharmacol Ther. 2008 Dec 1;28(11-12):1317-25. 
3. Skrovanek S, Valenzano MC, Mullin JM. Restriction of sulfur-containing amino acids alters claudin composition and improves tight junction barrier function. Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R1046-55. 
4. Mullin JM, Valenzano MC, Trembeth S, Allegretti PD, Verrecchio JJ, Schmidt JD, Jain V, Meddings JB, Mercogliano G, Thornton JJ. Transepithelial leak in Barrett's esophagus. Dig Dis Sci. 2006 Dec;51(12):2326-36. 
5. Mullin JM, Agostino N, Rendon-Huerta E, Thornton JJ. Keynote review: epithelial and endothelial barriers in human disease. Drug Discov Today. 2005 Mar 15;10(6):395-408. 
6. Mullin JM, Leatherman JM, Valenzano MC, Huerta ER, Verrechio J, Smith DM, Snetselaar K, Liu M, Francis MK, Sell C. Ras mutation impairs epithelial barrier function to a wide range of nonelectrolytes. Mol Biol Cell. 2005 Dec;16(12):5538-50. 
7. Mullin JM. 2004. Epithelial barriers, compartmentation and cancer. Science STKE Jan 13; 2004(216): pe2.
8. Rendon-Huerta E, Valenzano MC, Mullin JM, Trembeth SE, Kothari R, Hameed B, Mercogliano G, Thornton JJ. 2003. Comparison of three integral tight junction barrier proteins in Barrett's epithelium versus normal esophageal epithelium. Am J Gastroenterol. 98:1901-1903. 
9. Clarke, H., Peralta Soler, A., Mullin, J.M. 2000. Protein Kinase C Activation Leads to Dephosphorylation of Occludin and Tight Junction Permeability Increase in LLC-PK1 Epithelial Cell Sheets. J. Cell Sci. 113:3187-3196.
10. Peralta Soler, A., Miller, R.D, Laughlin, K.V., Carp, N.Z., Klurfeld, D.M. and Mullin, J.M. 1999. Increased Tight Junctional Permeability is Associated with the Development of Colon Cancer. Carcinogenesis 20:1425-1431.
11. Mullin, J.M., Kampherstein, J.A., Laughlin, K.V., Saladik, D.T., Peralta Soler, A. 1997. Transepithelial paracellular leakiness induced by chronic phorbol ester exposure correlates with polyp-like foci and redistribution of protein kinase C-alpha. Carcinogenseis 18:2339-2345.
12. Mullin, J.M., Laughlin, K.V., Marano, C.W., Russo, L.M., Peralta Soler, A. 1992. Modulation of tumor necrosis factor-induced increase in renal (LLC-PK1) transepithelial permeability. Am. J. Physiology 263:F915-F924. 
13. Mullin, J.M., O'Brien, T.G. 1986. Effect of tumor promoters on LLC-PK1 renal epithelial tight junctions and transepithelial fluxes. Am. J. Physiology 251:C597-C602