IBD is a group of chronic, relapsing inflammatory disorders of the gastrointestinal tract characterized by diarrhea, bleeding, abdominal pain, and weight loss. It can progress to serious complications due to severe inflammation, like intestinal perforation, fistula formation and/or toxic megacolon. The two main subtypes of IBD, Crohn's Disease and Ulcerative Colitis, afflict an estimated 1.1 million people in the US and represent two of the major gastrointestinal diseases of the Western world. Significantly, it is a disease that is primarily diagnosed in young adults, not only exacting an incalculable personal toll and annual economic cost in medical expenses, but also a considerable amount in lost productivity. There is an imperative need for identifying molecular targets relevant to the disease for better therapeutic approaches against IBD. Additionally, non-invasive diagnostic approaches need to be developed to facilitate the early diagnosis and therapeutic management of this chronic disease. Our studies focus on a novel, yet fundamental anti-inflammatory signaling pathway - TAM pathway - in antigen presenting cells (APCs) of the immune system and our objective is to better understand the function of this pathway in the context of this chronic, debilitating illness. Our goal is (i) to demonstrate an association between loss of TAM proteins and manifestation of severe disease employing established mouse models of this human disease, (ii) to understand the immunological dysfunction correlating with loss of these proteins functions and (iii) to subsequently extend these analyses beyond the pre-clinical mouse models to human patients and validate if TAM proteins can function as translational biomarkers for IBD. This project has the long-term potential to elucidate important molecular mechanisms underlying the clinical course of IBD, and to address important therapeutic and diagnostic/prognostic areas of need.

Public Health Relevance

The TAM proteins represent an entirely novel area of research in IBD, yet they belong to the class of enzymes that are well established as tractable pharmacological targets and are attractive for rational drug design and discovery. The ligands for the TAM receptors are plasma proteins affording easy detection as potential serum biomarkers of disease state/severity. Therefore, the proposed project has considerable potential to not only elucidate the molecular mechanisms underlying the clinical course of IBD and to uncover novel therapeutic targets, but also to address important diagnostic/prognostic area of need.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Rothermel, Annette L
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Yale University
Schools of Medicine
New Haven
United States
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Rothlin, Carla V; Leighton, Jonathan A; Ghosh, Sourav (2014) Tyro3, Axl, and Mertk receptor signaling in inflammatory bowel disease and colitis-associated cancer. Inflamm Bowel Dis 20:1472-80
Kusne, Yael; Carrera-Silva, Eugenio A; Perry, Anthony S et al. (2014) Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNF? in glioblastoma. Sci Signal 7:ra75
Bosurgi, Lidia; Bernink, Jochem H; Delgado Cuevas, Victor et al. (2013) Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer. Proc Natl Acad Sci U S A 110:13091-6
van den Brand, B T; Abdollahi-Roodsaz, S; Vermeij, E A et al. (2013) Therapeutic efficacy of Tyro3, Axl, and Mer tyrosine kinase agonists in collagen-induced arthritis. Arthritis Rheum 65:671-80
Bhattacharyya, Suchita; Zagorska, Anna; Lew, Erin D et al. (2013) Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors. Cell Host Microbe 14:136-47
Carrera Silva, Eugenio A; Chan, Pamela Y; Joannas, Leonel et al. (2013) T cell-derived protein S engages TAM receptor signaling in dendritic cells to control the magnitude of the immune response. Immunity 39:160-70