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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI089824-04
Application #
8515920
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
2010-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$376,805
Indirect Cost
$108,886
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chan, Pamela Y; Carrera Silva, Eugenio A; De Kouchkovsky, Dimitri et al. (2016) The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity. Science 352:99-103
Chae, Wook-Jin; Ehrlich, Allison K; Chan, Pamela Y et al. (2016) The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation. Immunity 44:246-58
Fourgeaud, Lawrence; Través, Paqui G; Tufail, Yusuf et al. (2016) TAM receptors regulate multiple features of microglial physiology. Nature 532:240-4
Rothlin, Carla V; Carrera-Silva, Eugenio A; Bosurgi, Lidia et al. (2015) TAM receptor signaling in immune homeostasis. Annu Rev Immunol 33:355-91
Bárcena, Cristina; Stefanovic, Milica; Tutusaus, Anna et al. (2015) Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation. J Hepatol 63:670-8
Cabezón, Raquel; Carrera-Silva, E Antonio; Flórez-Grau, Georgina et al. (2015) MERTK as negative regulator of human T cell activation. J Leukoc Biol 97:751-60
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 TNFα in glioblastoma. Sci Signal 7:ra75
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

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