A Murine Model of Chronic Autoimmune Hepatitis and Liver Fibrosis

自身免疫性肝炎（AIH）是一种病因不明的慢性门静脉炎症，如果控制不当，可导致肝硬化和肝功能衰竭。目前对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；此外，有相当一部分人没有回应。缺乏健壮的动物模型阻碍了对该病发病机制的理解和改进诊断和治疗的进展。二酰基甘油激酶（DGKs）通过磷酸化催化二酰基甘油转化为磷脂酸。我们和其他人最近证明了DGKa和？通过抑制T细胞受体（TCR）诱导的Ras和Erk1/2激活，负向控制T细胞活化。缺乏DGKa或？导致T细胞对TCR刺激反应过度，对能量诱导产生抗性。我们对这个应用的中心假设是DGKa和？协同促进肝脏的自我耐受性，T细胞耐受性的丧失和调节性T细胞（Tregs）的功能障碍有助于AIH的发病机制。有了强有力的初步数据，我们计划使用DGKa和？双重缺陷(DGKa？DKO)小鼠通过追求三个特定目标来验证我们的中心假设。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Aim 2中，我们将确定T细胞亚群在DGKa？DKO老鼠。在Aim 3中，我们将确定参与AIH发病机制的信号机制。拟议的研究应确立DGKa？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，并为该病的治疗提供了新的策略。公共卫生相关性：本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FOA PA-07-012“NIDDK相关疾病的动物模型”和NIDDK肝脏疾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.