James Mullin, PhD

Headshot of James Mullin, PhD

Resident Faculty

Professor

Dr. Mullin’s research focuses on the role of tight junctional leakiness in cancer, aging, infectious diseases and inflammatory diseases in the GI tract, respiratory tract, the oral epithelium and the lining of the uterus. He also is investigating the effect of micronutrient consumption/nutrition on reducing epithelial barrier leak, and the role of barrier (junctional) leak in infectious diseases such as Ebola, Marburg and coronaviruses.

About

  • 1986–Present: Professor, Lankenau Institute for Medical Research
  • 2002–Present: Director of Research, Department of Medicine, Division of Gastroenterology, Lankenau Medical Center
  • 2002–Present: Adjunct Professor, Department of Biology, St. Joseph's University
  • 2005–Present: Professor, Sidney Kimmel College of Medicine, Thomas Jefferson University
  • 2011–Present: Editorial Board, The Journal of Gastroenterology and Hepatology Research
  • 2011–Present: Editorial Board, The Scientific World Journal
  • 2012–Present: Editorial Board, Gastrointestinal Cancer: Targets and Therapy
  • 2015–Present: Editorial Board, Austin Journal of Gastroenterology
  • 2018–Present: Editorial Board, World Journal of Gastrointestinal Pharmacology and Therapeutics

Research Descriptions

Background

The epithelium is the cellular covering of internal and external body surfaces, including the lining of vessels and small cavities. It consists of cells joined by small amounts of gasket-like proteinaceous sealing strands—and looks very much like the view you see when you look down at a tile floor.

While epithelial linings found throughout the body are unique to the given organ/tissue, all function to separate two internal compartments: lumen and bloodstream. The luminal side of an epithelial layer/barrier communicates directly or indirectly with the outside environment, e.g., food material in the digestive tract or newly breathed air in the lungs. The other compartment, the bloodstream, is the pristine fluid space that houses, for example, red blood cells and the immune system.

The epithelial lining’s first and most important function is to act as a barrier to separate those two compartments. If there’s a compromise of the barrier function—that is, if the junctional seals become leaky—it can lead to medical problems such as inflammation.

Studies of zinc

Dr. Mullin’s research group, which bridges LIMR and the Division of Gastroenterology of Lankenau Medical Center, focuses on the tight junctions—the gasket-like seals—between the individual epithelial cells that make up the lining of the digestive tract, and how they become leaky in the early stage of gastrointestinal (GI) cancer, many infectious diseases, Barrett’s esophagus, and inflammatory bowel diseases (e.g., Crohn’s disease, ulcerative colitis, celiac disease).

Several years ago, researchers discovered beneficial changes in epithelial linings in the presence of certain micronutrients. Dr. Mullin’s team is investigating how lack of one of those nutrients, zinc, affects numerous disease processes by reducing leak of the epithelial tight junctions.

Barrett’s esophagus: Arising from chronic heartburn or gastroesophageal reflux disease, Barrett’s esophagus impacts one to two percent of adults in the United States. It is too often a precursor to cancer of the esophagus, which has a very high mortality 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. He and his collaborators have patented and are preparing to license out the intellectual property for using zinc as a cancer preventive in Barrett’s esophagus.

Crohn’s disease and ulcerative colitis: Dr. Mullin’s lab is also examining whether micronutrients can reduce tight junctional leak and therefore have therapeutic application in treating these GI inflammatory diseases. His group uses both cell culture studies and patient-based studies in this overall project.

Infectious diseases: His lab also is performing preclinical investigations on whether tightened epithelial junctions can help ward off infection with pathogens such as ebola virus and HIV. Specifically, they are trying to determine if low zinc levels make the epithelial lining more porous, thus making it more likely that a virus such as HIV, hepatitis C or HPV can penetrate an epithelial barrier that it contacts and thereby enter the patient’s bloodstream.

About his lab

Dr. Mullin’s lab performs combinations of studies with epithelial cell cultures grown in the lab, with animal epithelial tissues, human epithelial tissues and different classes of patients with gastrointestinal diseases. The focus is always on the barrier function of the epithelial cell layer, the disease processes that make these layers leaky, and the newly discovered ability of certain micronutrients to make them less leaky.

Phase 1 clinical studies being performed with Lankenau’s Division of Gastroenterology are underway in Barrett’s esophagus and reflux disease. Preclinical studies are examining the micronutrient modification of epithelial tight junctions on a molecular level, and the effect of these changes on inhibition of viral invasion across epithelial barriers. Recent work with the Wistar Institute of the University of Pennsylvania is examining the action of zinc in semen in inducing modification and improvement of epithelial junctions, and thereby reducing infection by STDs.

Lab personnel

  • Elizabeth Scimeca, MS, Research Technician
  • Carmen Valenzano, Research Lab Associate
  • Katherine DiGuilio, DO, Postdoctoral Fellow
  • Elizabeth Richardson, Gastroenterology Fellow
  • Silpa Yalamanchili, Gastroenterology Fellow
  • Kiley Leroy, Gastroenterology Fellow
  • Vida Chen, Gastroenterology Fellow

Publications

  • Quercetin improves and protects Calu-3 airway epithelial barrier function. DiGuilio KM, Rybakovsky E, Valenzano MC, … Del Rio EA, … Mullin JM. Front Cell Dev Biol. 2023 Nov 23;11:1271201. doi: 10.3389/fcell.2023.1271201
  • Calcitriol modifies tight junctions, improves barrier function, and reduces TNF-α-induced barrier leak in the human lung-derived epithelial cell culture model, 16HBE 14o. Rybakovsky E, DiGuilio KM, Valenzano MC, Geagan S, Pham K, Harty RN, Mullin JM. Physiol Rep. 2023 Apr;11(7):e15592. doi: 10.14814/phy2.15592
  • The multiphasic TNF-α-induced compromise of Calu-3 airway epithelial barrier function. DiGuilio KM, Rybakovsky E, Baek Y, Valenzano MC, Mullin JM. Exp Lung Res. 2023;49(1):72-85
  • Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy. DiGuilio KM, Rybakovsky E, … Chamoun R, … Mullin JM. Int. J. Mol. Sci. 2022, 23(6), 2995-3037.
  • SARS-CoV-2 Envelope (E) protein interacts with PDZ-domain-2 of host tight junction protein ZO1. Shepley-McTaggart A, Sagum CA, … Rybakovsky E, DiGuilio K, … Mullin JM, Harty RN.PLoS One. 2021 Jun 9;16(6):e0251955.
  • Retinoic acid improves baseline barrier function and attenuates TNF-α-induced barrier leak in human bronchial epithelial cell culture model, 16HBE 14o. Callaghan PJ, Rybakovsky E, Ferrick B, Thomas S, Mullin JM. PLoS One. 2020 Dec 10;15(12):e0242536.
  • Epithelial barrier function properties of the 16HBE14o- human bronchial epithelial cell culture model. Callaghan PJ, Ferrick B, Rybakovsky E, Thomas S, Mullin JM. Biosci Rep. 2020 Oct 30;40(10):BSR20201532.
  • Zinc Gluconate Induces Potentially Cancer Chemopreventive Activity in Barrett's Esophagus: A Phase 1 Pilot Study. Valenzano MC, Rybakovsky E, Newman G, Mercogliano G, Etemad B, Mullin JM, et al. Dig Dis Sci. 2020 May 15. Dig Dis Sci. 2021 Apr;66(4):1195-1211.
  • Improving Transient Transfection Efficiency in a Differentiated, Polar Epithelial Cell Layer. Rybakovsky E, Valenzano MC, DiGuilio KM, … Mullin JM. J Biomol Tech. 2019 Apr 19.
  • Spontaneous and cytokine-induced hole formation in epithelial cell layers: Implications for barrier function studies with the gingival cell culture, Gie-3B11, and other epithelial models. Rybakovsky E, Buleza NB, Hoxha K, DiGuilio KM, ... Thomas S, Mullin JM. Trends in Cell & Molecular Biology. 2018. 13:99-114.
  • Intestinal barrier tightening by a cell-penetrating antibody to Bin1, a candidate target for immunotherapy of ulcerative colitis. Thomas S, Hoxha K, Alexander W, Gilligan J, Dilbarova R, Whittaker K, Kossenkov A, Prendergast GC, Mullin JM. J Cell Biochem. 2018 Sep 30. doi: 10.1002/jcb.27716.
  • Cobalt chloride compromises transepithelial barrier properties of CaCo-2 BBe human gastrointestinal epithelial cell layers. DiGuilio KM, Valenzano MC, Rybakovsky E, Mullin JM. BMC Gastroenterol. 2018 Jan 5;18(1):2.
  • Improvement of Human-Oral-Epithelial-Barrier Function and of Tight Junctions by Micronutrients. Rybakovsky E, Valenzano MC, Deis R, DiGuilio KM, Thomas S, Mullin JM. J Agric Food Chem. 2017 Dec 20;65(50):10950-58.
  • The Host Microbiome Regulates and Maintains Human Health: A Primer and Perspective for Non-Microbiologists. Thomas S, Izard J, Walsh E, Batich K, Chongsathidkiet P, Clarke G, Sela DA, Muller AJ, Mullin JM, Albert K, Gilligan JP, DiGuilio K, Dilbarova R, Alexander W, Prendergast GC. Cancer Res. 2017 Mar 14.
  • Zinc reduces epithelial barrier compromise induced by human seminal plasma. Mullin JM, Diguilio KM, Valenzano MC, Deis R, Thomas S, Zurbach EP, Abdulhaqq S, Montaner LJ. PLoS One. 2017 Mar 9;12(3):e0170306.
  • Sieving characteristics of cytokine- and peroxide-induced epithelial barrier leak: Inhibition by berberine. DiGuilio KM, Mercogliano CM, Born J, Ferraro B, To J, Mixson B, Smith A, Valenzano MC, Mullin JM. World J Gastrointest Pathophysiol. 2016 May 15;7(2):223-34.
  • Remodeling of Tight Junctions and Enhancement of Barrier Integrity of the CACO-2 Intestinal Epithelial Cell Layer by Micronutrients. Valenzano MC, DiGuilio K, Mercado J, ..., Mullin JM. PLoS One. 2015 Jul 30;10(7):e0133926.
  • Novel Colitis Immunotherapy Targets Bin1 and Improves Colon Cell Barrier Function. Thomas S, Mercado JM, DuHadaway J, DiGuilio K, Mullin JM, Prendergast GC. Dig Dis Sci. 2015 Jul 21.
  • Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling. Pawlikowski JS, Brock C, Chen SC, ..., Mullin JM, et al. J Invest Dermatol. 2015 Aug;135(8):2093-101.
  • Retrofitting the battlements: tight junction remodeling as a novel antimicrobial approach. Mullin JM, Raines J, Livornese LL Jr. Future Med Chem. 2015;7(1):9-13.
  • Zinc and gastrointestinal disease. Skrovanek S, DiGuilio K, Bailey R, Huntington W, Urbas R, Mayilvaganan B, Mercogliano G, Mullin JM. World J Gastrointest Pathophysiol. 2014 Nov 15;5(4):496-513.
  • Methionine restriction fundamentally supports health by tightening epithelial barriers. Mullin JM, Skrovanek SM, Ramalingam A, DiGuilio KM, Valenzano MC. Ann N Y Acad Sci. 2015 Dec 8. doi: 10.1111/nyas.12955. [Epub ahead of print]
  • Drug delivery of zinc to Barrett's metaplasia by oral administration to Barrett's esophagus patients. Valenzano MC, Mercado JM, Wang X, ... Mercogliano G, Mullin JM, et al. Ther Deliv. 2014 Mar;5(3):257-64.
  • Zinc enhancement of LLC-PK(1) renal epithelial barrier function. Wang X, Valenzano MC, Mercado JM, Zurbach EP, Flounders CJ, Mullin JM. Clin Nutr. 2014 Apr;33(2):280-6.
  • Enhancement of tight junctional barrier function by micronutrients: compound-specific effects on permeability and claudin composition. Mercado J, Valenzano MC, Jeffers C,... Mullin JM, et al. PLoS One. 2013 Nov 13;8(11):e78775.
  • Zinc Supplementation Modifies Tight Junctions and Alters Barrier Function of CACO-2 Human Intestinal Epithelial Layers. X Wang, MC Valenzano, JM Mercado, EP Zurbach, JM Mullin. Dig Dis Sci. 2013;58:77-87.
  • Dietary methionine restriction improves colon tight junction barrier function and alters claudin expression pattern. A Ramalingam, X Wang, M Gabello, MC Valenzano, AP Soler, A Ko, PJ Morin, JM Mullin. Am J. Physiol Cell Physiol. 2010; 299:1028-35.
  • Epithelial and endothelial barriers in human disease. JM Mullin, N Agostino, E Rendon-Herta, JJ Thornton. Drug Discover Today. 2005;10(6):395-408.
  • Epithelial Barriers, Compartmentation and Cancer. JM Mullin. Sci STKE 2004. Jan 13;2004(216):pe2. Review.
  • Increased right junctional permeability is associated with the development of colon cancer. AP Soler, RD Miller, KV Laughlin, NZ Carp, DM Klurfeld, JM Mullin. Carcinogenesis. 1999;20(8):1425-1431.
  • Transepithelial paracellular leakiness induced by chronic phorbol ester exposure correlates with polyp-like foci and redistribution of protein kinase C-alpha. JM Mullin, JA Kampherstein, KV Laughlin, DT Saladik, AP Soler. Carcinogenesis. 1997;18(12):2339-2345.
  • Effect of Tumor Necrosis Factor on Epithelial Tight Junctions and Transepithelial Permeability. JM Mullin, KV Snock. Cancer Research. 1990;50:2172-2176.
  • Effects of tumor promoters on LLC-PK1 renal epithelial tight junctions and transepithelial fluxes. JM Mullin, TG O’Brien. Am J Physiol. 1986 Oct;251(4 Pt 1):C597-602.

Education and Training

Education

  • Postdoctoral BS, Biology
    Saint Joseph College
  • Postdoctoral PhD, Physiology
    University of Pennsylvania
  • Postdoctoral Fellowship
    The Wistar Institute
  • Postdoctoral Fellow, Human Genetics
    Yale University School of Medicine

Academic Titles

  • 1986–Present: Professor, Lankenau Institute for Medical Research
  • 2002–Present: Director of Research, Department of Medicine, Division of Gastroenterology, Lankenau Medical Center
  • 2002–Present: Adjunct Professor, Department of Biology, St. Joseph's University
  • 2005–Present: Professor, Sidney Kimmel College of Medicine, Thomas Jefferson University
  • 2011–Present: Editorial Board, The Journal of Gastroenterology and Hepatology Research
  • 2011–Present: Editorial Board, The Scientific World Journal
  • 2012–Present: Editorial Board, Gastrointestinal Cancer: Targets and Therapy
  • 2015–Present: Editorial Board, Austin Journal of Gastroenterology
  • 2018–Present: Editorial Board, World Journal of Gastrointestinal Pharmacology and Therapeutics