Inflammatory bowel diseases (IBD) are the result of complex interactions between susceptibility and severity genes, the environment and the mucosal immune system. These interactions lead to an exaggerated mucosal immune response to constituents of the commensal flora. With the advent of high-throughput molecular technologies, several genome wide association studies (GWAS) have begun to define critical molecules and pathways that converge in physiologic processes that lead to mucosal inflammation. This technique can also be used to focus in vivo mouse studies for eventual development of targeted therapeutics for defined subsets of Crohn's disease (CD) patients. Tumor necrosis factor superfamily member 15 (TNFSF15) is the only one of the several recently discovered CD associated genes that is present in all ethnic groups. The product of the TNFSF15 gene, TL1A, has been defined as a master regulatory protein that plays a key role in human intestinal inflammation. Recent studies have also defined a critical role for TL1A in the pathogenesis of mouse experimental autoimmune encephalomyelitis (EAE), models of allergic lung inflammation and human rheumatoid arthritis. During the last grant cycle, we have generated a large body of data showing the importance of TL1A in human CD. We determined that TL1A is elevated in lamina propria mononuclear cells from the mucosa of patients with CD but the level varies among individual patients with similar amounts of inflammation. GWAS established that TNFSF15 is a CD susceptibility/severity gene. We demonstrated that antibodies to TL1A prevented and treated chronic colitis by decreasing Th1 and Th17 responses in two T cell mediated mouse models, confirming a role for TL1A in severity of inflammation. Finally, we found that the level TL1A protein expression varies in association with different CD genotypes, as defined by ethnic background, haplotype and serum antibody responses. Our hypothesis is that myeloid (antigen presenting cell, APC) generation of TL1A is a dominant event that determines the severity of chronic intestinal inflammation by enhancing intestinal Th1 and Th17 responses, leading to exacerbated inflammation in CD. Further elucidation of the in vivo cellular and molecular mechanisms of TL1A function in mucosal inflammation, the mechanisms of optimal bacterial induction of TL1A, and the relationship of genetic variation in the TNFSF15 gene to maximal ligand induced TL1A protein expression will help us to identify subsets of CD patients most likely to benefit from therapeutic inhibition of TL1A function. The following Specific Aims will test this hypothesis.1) Determine the in vivo role of myeloid v. T cell expression of TL1A in the development and severity of chronic colitis in the mouse. 2) Determine the roles of endocytosis and autophagy in the bacterial induction of maximal TL1A expression in human and murine (myeloid) APC. 3) Determine the relationship between variants in the CD associated TNFSF15 gene and the level of expression of TL1A mRNA and protein in human myeloid cell populations.

Public Health Relevance

Inflammatory bowel diseases (IBD) affects more than 1,000,000 Americans. The studies of the role of Tumor necrosis factor superfamily member 15 (TNFSF15, TL1A) in severity of inflammation in Crohn's disease potentially could lead to the development of targeted therapeutics for a defined patient subpopulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056328-14
Application #
8312725
Study Section
Special Emphasis Panel (ZRG1-DKUS-F (02))
Program Officer
Hamilton, Frank A
Project Start
1999-08-20
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
14
Fiscal Year
2012
Total Cost
$418,264
Indirect Cost
$160,871
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Shih, D Q; Zheng, L; Zhang, X et al. (2014) Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis. Mucosal Immunol 7:1492-503
Zheng, Libo; Zhang, Xiaolan; Chen, Jeremy et al. (2013) SUSTAINED TL1A (TNFSF15) EXPRESSION ON BOTH LYMPHOID AND MYELOID CELLS LEADS TO MILD SPONTANEOUS INTESTINAL INFLAMMATION AND FIBROSIS. Eur J Microbiol Immunol (Bp) 3:11-20
Vora, Puja; Shih, David Quan; McGovern, Dermot Patrick et al. (2012) Current concepts on the immunopathogenesis of inflammatory bowel disease. Front Biosci (Elite Ed) 4:1451-77
Barrett, Robert; Zhang, Xiaolan; Koon, Hon Wai et al. (2012) Constitutive TL1A expression under colitogenic conditions modulates the severity and location of gut mucosal inflammation and induces fibrostenosis. Am J Pathol 180:636-49
Shih, David Q; Barrett, Robert; Zhang, Xiaolan et al. (2011) Constitutive TL1A (TNFSF15) expression on lymphoid or myeloid cells leads to mild intestinal inflammation and fibrosis. PLoS One 6:e16090
Muller, Marioly; Cardenas, Cesar; Mei, Lijuan et al. (2011) Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP3R) Ca2+ signaling. Proc Natl Acad Sci U S A 108:13293-8
Shih, David Q; Michelsen, Kathrin S; Barrett, Robert J et al. (2011) Insights into TL1A and IBD pathogenesis. Adv Exp Med Biol 691:279-88
Nguyen, Minh; Bradford, Kara; Zhang, Xiaolan et al. (2011) Cytomegalovirus Reactivation in Ulcerative Colitis Patients. Ulcers 2011:
Cardenas, Cesar; Miller, Russell A; Smith, Ian et al. (2010) Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 142:270-83
Eckenrode, Emily F; Yang, Jun; Velmurugan, Gopal V et al. (2010) Apoptosis protection by Mcl-1 and Bcl-2 modulation of inositol 1,4,5-trisphosphate receptor-dependent Ca2+ signaling. J Biol Chem 285:13678-84

Showing the most recent 10 out of 29 publications