The Lankenau Institute for Medical Research
Association: Resident Faculty
About his work
Dr. Mullin’s research focuses on the role of gastrointestinal (tight junctional) leakiness in cancer, aging, infectious diseases and inflammatory diseases. He also is investigating the effect of micronutrient consumption/nutrition on reducing tight junctional (epithelial barrier) leak.
Awards and honors
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.
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.
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.
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, Teter M, To J, Ferraro B, Mixson B, Manley I, Baker V, Moore BA, Wertheimer 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, Al-Olabi L, Nixon C, McGregor F, Paine S, Chanudet E, Lambie W, Holmes WM, Mullin JM, Richmond A, Wu H, Blyth K, King A, Kinsler VA, Adams PD. 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, Zurbach EP, Raines J, McDonnell E, Morgan M, Farrell C, Rudolph D, Hwang A, Barr M, Cherian D, Bailey R, Raile B, Albert N, Thornton J, Zitin M, Abramson J, Newman G, Daum G, Mercogliano G, Mullin JM. 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, Sedlak J, Cugliari MK, Papanikolaou E, Clouse J, Miao J, Wertan NE, Mullin JM. PLoS One. 2013 Nov 13;8(11):e78775.