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.
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.
|Del Carmen, Silvina; Hapak, Sophie M; Ghosh, Sourav et al. (2018) Coagulopathies and inflammatory diseases: '…glimpse of a Snark'. Curr Opin Immunol 55:44-53|
|Mulla, Melissa J; Weel, Ingrid C; Potter, Julie A et al. (2018) Antiphospholipid Antibodies Inhibit Trophoblast Toll-Like Receptor and Inflammasome Negative Regulators. Arthritis Rheumatol 70:891-902|
|Hughes, Lindsey D; Bosurgi, Lidia; Ghosh, Sourav et al. (2017) Chronicles of Cell Death Foretold: Specificities in the Mechanism of Disposal. Front Immunol 8:1743|
|Akalu, Yemsratch T; Rothlin, Carla V; Ghosh, Sourav (2017) TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy. Immunol Rev 276:165-177|
|Gómez-Galván, J B; Borrego, S; Tovar, N et al. (2017) Nilotinib as a risk factor for ischaemic stroke: A series of three cases. Neurologia 32:411-413|
|Uribe, Diana J; Mandell, Edward K; Watson, Adam et al. (2017) The receptor tyrosine kinase AXL promotes migration and invasion in colorectal cancer. PLoS One 12:e0179979|
|Cross, Sarah N; Potter, Julie A; Aldo, Paulomi et al. (2017) Viral Infection Sensitizes Human Fetal Membranes to Bacterial Lipopolysaccharide by MERTK Inhibition and Inflammasome Activation. J Immunol 199:2885-2895|
|DeBerge, Matthew; Yeap, Xin Yi; Dehn, Shirley et al. (2017) MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury. Circ Res 121:930-940|
|Bosurgi, Lidia; Cao, Y Grace; Cabeza-Cabrerizo, Mar et al. (2017) Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science 356:1072-1076|
|A-Gonzalez, Noelia; Quintana, Juan A; García-Silva, Susana et al. (2017) Phagocytosis imprints heterogeneity in tissue-resident macrophages. J Exp Med 214:1281-1296|
Showing the most recent 10 out of 28 publications