Dr. Moss is a junior investigator in Inflammatory Bowel Disease (IBD). As a fellow he trained in the molecular biology of inflammation, in addition to his clinical training as a gastroenterologist. In the last 2 years he has been mentored by Dr Simon Robson in immunology research methods. His immediate goal is to further develop his immunology and research training in translational research in order to investigate the role of endogenous immuno-suppressive pathways in IBD. The development of future diagnostic and therapeutic tools for patients with these diseases will require investigators who can bring advances in immunology to the bed-side, and vice versa. His medium- term goal is to acquire suitable preliminary data for a successful R01-application in this field, and establish his reputation through relevant scholarly activities. In the long-term Dr Moss intends to obtain consistent funding to maintain an independent laboratory group focused on translational research in novel therapeutics and diagnostic methods in IBD. The research career development plan for this K23 is based on a combination of an outstanding mentor in immunology (Dr Simon Robson), a Career Development Committee of investigators with strong translational research resumes, and specific coursework tailored to foster Dr Moss's pathway to independence. The host institution (BIDMC) have demonstrated their on-going commitment to Dr Moss through his promotion to junior faculty and Assistant Professor, the continued provision of laboratory space, protected research time (salary support), and dedicated mentorship for him. The Dept of Medicine and Division of Gastroenterology have limited his clinical workload with the primary intention of allowing him appropriate time for laboratory experience, coursework and academic networking. The proposed project is not only a topic of profound clinical importance but also an ideal training vehicle in which Dr Moss will have the opportunity to solidify his existing skills and to learn new research techniques. The purpose of this K23 proposal by Dr Alan Moss is to examine the mechanisms through which one pathway of immune regulation is altered in patients with Crohn's disease, and how certain treatments modify this effect. In particular, this proposal will study a group of enzymes (CD39, CD73) and receptors that convert harmful products of tissue damage (ATP, ADP) to immuno- suppressive molecules (adenosine). Studies in animal models have suggested that these enzymes are protective against inflammation, but their role in human Crohn's disease is unknown. Preliminary data by Dr Moss has observed an alteration in the proportion and activity of these enzymes in patients with Crohn's disease. The experiments in this proposal will quantify the presence and activity of these purinergic pathways in patients with Crohn's disease, and healthy controls. We will examine how inflammatory states may impair their action, and how treatment with certain drugs (anti- TNF agents) modifies their activity. This project aims to provide a thorough understanding of these pathways in patients with Crohn's disease, so that novel treatments may be developed to enhance their immuno-suppressive roles.

Public Health Relevance

Inflammatory Bowel Disease affects nearly 2 million Americans. This proposal will improve our understanding of regulation of the immune system in patients with Crohn's disease. It may provide novel targets for drug treatments for patients with this condition.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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Beth Israel Deaconess Medical Center
United States
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Gubatan, John; Mitsuhashi, Shuji; Longhi, Maria Serena et al. (2018) Higher serum vitamin D levels are associated with protective serum cytokine profiles in patients with ulcerative colitis. Cytokine 103:38-45
Samudra, Anushka N; Dwyer, Karen M; Selan, Carly et al. (2018) CD39 and CD73 activity are protective in a mouse model of antiphospholipid antibody-induced miscarriages. J Autoimmun 88:131-138
Gubatan, John; Mitsuhashi, Shuji; Zenlea, Talia et al. (2017) Low Serum Vitamin D During Remission Increases Risk of Clinical Relapse in Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol 15:240-246.e1
Longhi, Maria Serena; Vuerich, Marta; Kalbasi, Alireza et al. (2017) Bilirubin suppresses Th17 immunity in colitis by upregulating CD39. JCI Insight 2:
Feldbr├╝gge, Linda; Moss, Alan C; Yee, Eric U et al. (2017) Expression of Ecto-nucleoside Triphosphate Diphosphohydrolases-2 and -3 in the Enteric Nervous System Affects Inflammation in Experimental Colitis and Crohn's Disease. J Crohns Colitis 11:1113-1123
Mitsuhashi, Shuji; Feldbr├╝gge, Linda; Csizmadia, Eva et al. (2016) Luminal Extracellular Vesicles (EVs) in Inflammatory Bowel Disease (IBD) Exhibit Proinflammatory Effects on Epithelial Cells and Macrophages. Inflamm Bowel Dis 22:1587-95
Vaughn, Byron P; Vatanen, Tommi; Allegretti, Jessica R et al. (2016) Increased Intestinal Microbial Diversity Following Fecal Microbiota Transplant for Active Crohn's Disease. Inflamm Bowel Dis 22:2182-90
Bai, Aiping; Moss, Alan; Rothweiler, Sonja et al. (2015) NADH oxidase-dependent CD39 expression by CD8(+) T cells modulates interferon gamma responses via generation of adenosine. Nat Commun 6:8819
Abhyankar, Anita; Moss, Alan C (2015) Iron Replacement in Patients with Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Inflamm Bowel Dis 21:1976-81
Moss, Alan C (2014) The meaning of low-grade inflammation in clinically quiescent inflammatory bowel disease. Curr Opin Gastroenterol 30:365-9

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