A Murine Model of Chronic Autoimmune Hepatitis and Liver Fibrosis

摘要 自身免疫性肝炎(AIH)是一种病因不明的慢性门脉炎症，可导致 如果控制不当，会导致肝硬变和肝功能衰竭。目前AIH的治疗依赖于长期的全身治疗 免疫抑制。然而，这种疗法会使患者面临严重副作用的风险；此外， 相当大的少数人没有回应。由于缺乏针对这种疾病的强有力的动物模型， 了解该病的发病机制，提高诊断和治疗水平的进展。 二酰基甘油酶(DGKs)通过以下途径催化二酰基甘油转化为磷脂酸 磷酸化。我们和其他人最近证明了DGK和？的异构体在T中表达 细胞，通过抑制T细胞受体(TCR)诱导的RAS和ERK1/2来负向控制T细胞的激活 激活。DGK或DGK缺乏会导致T细胞对TCR刺激和 抵抗无能诱导。我们对这一应用的中心假设是DGK和DGK 协同作用有助于对肝脏的自我耐受以及T细胞耐受性的丧失和 调节性T细胞(Tregs)参与了AIH的发病。有了强劲的初步数据，我们计划 使用DGK和DGK双缺陷(DGK？DKO)小鼠来测试我们的中心假设，通过追求三个 明确的目标。在目标1中，我们将DGK？DKO小鼠定义为慢性AIH和肝脏的相关模型 纤维化症。在目标2中，我们将确定T细胞亚群在DGK肝炎发病机制中的作用 DKO小鼠。在目标3中，我们将确定参与糖尿病发病机制的信号机制。 啊哈。建议的研究应建立DGK？DKO小鼠作为慢性AIH和 肝纤维化，提高对AIH发病机制的了解，并提供 针对这种疾病的新治疗策略。项目叙事 这项拨款申请旨在建立期待已久的慢性自身免疫性肝炎小鼠模型，并 肝纤维化，与FOA PA-07-012直接相关，标题为‘NIDDK相关动物模型 疾病的研究和NIDDK肝病研究行动计划。拟议的研究预计将 提高对自身免疫性肝炎发病机制的认识并提供治疗策略 AIH和其他自身免疫性疾病。

ABSTRACT 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 DGK¿ 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 DGK¿ or ¿ causes T cells to be hyperresponsive to TCR stimulation and resistant to anergy induction. Our central hypotheses for this application are that DGK¿ and ¿ synergistically contribute to self-tolerance to the liver and that loss of T cell-tolerance and dysfunction of regulatory T cells (Tregs) contribute to the pathogenesis of AIH. With strong preliminary data, we plan to use DGK¿ and ¿ doubly deficient (DGK¿¿ DKO) mice to test our central hypotheses by pursuing three specific aims. In aim 1, we will define DGK¿¿ 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 DGK¿¿ DKO mice. In aim 3, we will determine the signaling mechanisms that participate in the pathogenesis of AIH. The proposed studies should establish DGK¿¿ 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. PROJECT NARRATIVE 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.