A Murine Model of Chronic Autoimmune Hepatitis and Liver Fibrosis

描述(申请人提供)：自身免疫性肝炎(AIH)是一种原因不明的慢性门脉炎症，如果控制不当，可能会导致肝硬化和肝功能衰竭。目前AIH的治疗依赖于长期的全身免疫抑制。然而，这种疗法使患者面临严重副作用的风险；而且，相当少数人没有反应。这种疾病缺乏强有力的动物模型，阻碍了在了解该病的发病机制以及改进诊断和治疗方面的进展。甘油二酯激酶(DGKs)通过磷酸化催化甘油二酯转化为磷脂酸。我们和其他人最近证明，在T细胞中表达的DGKA和β亚型通过抑制T细胞受体(TCR)诱导的RAS和ERK1/2的激活来负向控制T细胞的激活。DGKA缺乏症或？使T细胞对TCR刺激高度反应，并抵抗无能诱导。我们对这一应用的中心假设是DGKA和？协同作用有助于肝脏的自我耐受，而T细胞耐受性的丧失和调节性T细胞(Tregs)的功能障碍是AIH的发病原因。有了强劲的初步数据，我们计划使用DGKA和？双缺位(DGKA？DKO)小鼠通过追求三个特定目标来测试我们的中心假设。在目标1中，我们将定义DGKA？DKO小鼠作为慢性AIH和肝纤维化的相关模型。在目标2中，我们将确定T细胞亚群在DGKA？DKO小鼠。在目标3中，我们将确定参与AIH发病机制的信号机制。建议的研究应该建立DGKA吗？DKO小鼠作为慢性AIH和肝纤维化的合适模型，提高了对AIH发病机制的认识，为AIH的治疗提供了新的策略。公共卫生相关性：这项拨款申请旨在建立期待已久的慢性自身免疫性肝炎和肝纤维化小鼠模型，并与题为“NIDDK相关疾病的动物模型”的FOA PA-07-012和NIDDK肝病研究行动计划直接相关。这些研究有望提高对自身免疫性肝炎发病机制的认识，并为AIH和其他自身免疫性疾病提供治疗策略。

DESCRIPTION (provided by applicant): 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.