Autoimmune hepatitis (AIH) is a chronic portal inflammation of unknown etiology that can lead to cirrhosis and liver failure if not properly controlled. Current treatment of AIH relies on long-term systemic immune suppression. However, such therapy places patients at risk of severe side effects;moreover, a significant minority does not respond. The lack of a robust animal model for the disease has hampered progress in understanding the pathogenesis of this disease and improving diagnosis and treatment. Diacylglycerol kinases (DGKs) catalyze the conversion of diacylglycerol to phosphatidic acid through phosphorylation. We and others have recently demonstrated that DGKa and ?, isoforms expressed in T cells, negatively control T cell activation by inhibiting T cell receptor (TCR)-induced Ras and Erk1/2 activation. Deficiency of either DGKa or ? causes T cells to be hyperresponsive to TCR stimulation and resistant to anergy induction. Our central hypotheses for this application are that DGKa and ? synergistically contribute to self-tolerance to the liver and that loss of T cell-tolerance and dysfunction of regulatory T cells (Tregs) contributes to the pathogenesis of AIH. With strong preliminary data, we plan to use DGKa and ? doubly deficient (DGKa? DKO) mice to test our central hypotheses by pursuing three specific aims.
In Aim 1, we will define DGKa? DKO mice as a relevant model for chronic AIH and liver fibrosis.
In Aim 2, we will determine the role of T cell subsets in the pathogenesis of hepatitis in DGKa? DKO mice.
In Aim 3, we will determine the signaling mechanisms that participate in the pathogenesis of AIH. The proposed studies should establish DGKa? DKO mice as a proper model for chronic AIH and liver fibrosis, improve understanding of the mechanisms involved in the pathogenesis of AIH, and provide new therapeutic strategies for the disease. Public Health Relevance: This grant application aims to establish a long-awaited murine model of chronic autoimmune hepatitis and liver fibrosis and is directly relevant to FOA PA-07-012 entitled 'Animal Models of NIDDK Relevant Diseases'and to the NIDDK Liver Diseases Research Action Plan. The proposed studies are expected to improve understanding of the pathogenesis of autoimmune hepatitis and provide therapeutic strategies for AIH and other autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI076357-03
Application #
7891264
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Rothermel, Annette L
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
3
Fiscal Year
2010
Total Cost
$308,880
Indirect Cost
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Yang, Wei; Gorentla, Balachandra; Zhong, Xiao-Ping et al. (2015) mTOR and its tight regulation for iNKT cell development and effector function. Mol Immunol 68:536-45
Ci, Xinxin; Kuraoka, Masayuki; Wang, Hongxia et al. (2015) TSC1 Promotes B Cell Maturation but Is Dispensable for Germinal Center Formation. PLoS One 10:e0127527
You, Jae-Sung; Lincoln, Hannah C; Kim, Chan-Ran et al. (2014) The role of diacylglycerol kinase ? and phosphatidic acid in the mechanical activation of mammalian target of rapamycin (mTOR) signaling and skeletal muscle hypertrophy. J Biol Chem 289:1551-63
Krishna, Sruti; Yang, Jialong; Wang, Hongxia et al. (2014) Role of tumor suppressor TSC1 in regulating antigen-specific primary and memory CD8 T cell responses to bacterial infection. Infect Immun 82:3045-57
Mousallem, Talal; Yang, Jialong; Urban, Thomas J et al. (2014) A nonsense mutation in IKBKB causes combined immunodeficiency. Blood 124:2046-50
Wu, Jinhong; Yang, Jialong; Yang, Kai et al. (2014) iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions. J Clin Invest 124:1685-98
Wu, Jinhong; Shin, Jinwook; Xie, Danli et al. (2014) Tuberous sclerosis 1 promotes invariant NKT cell anergy and inhibits invariant NKT cell-mediated antitumor immunity. J Immunol 192:2643-50
Shin, Jinwook; Wang, Shang; Deng, Wenhai et al. (2014) Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function. Proc Natl Acad Sci U S A 111:E776-83
Krishna, Sruti; Zhong, Xiaoping (2013) Role of diacylglycerol kinases in T cell development and function. Crit Rev Immunol 33:97-118

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