Mechanism of NOD.IDD3/10/17/18/9(LD) Liver Disease

NOD.IDD3/10/17/18/9(LD)肝病的机制

• 批准号: 6765824
• 负责人: William M Ridgway
• 金额: $ 21.37万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6765824
• 关键词: B lymphocyte; NOD mouse; T lymphocyte; antibody formation; autoantibody; autoimmune disorder; biliary tract disorder; cellular pathology; disease /disorder model; genetic susceptibility; leukocyte activation /transformation; liver disorder; model design /development; molecular pathology; pathologic process; pyruvate dehydrogenase; tissue /cell culture

DESCRIPTION (provided by applicant): The goal of this proposal is to determine mechanisms of a novel autoimmune and biliary tract disease discovered in the NOD.ldd3/10/17/18/9(LD) mouse. The Nonobese diabetic (NOD) mouse is an animal model of spontaneous, genetically complex autoimmune diabetes. NOD mice develop lymphocytic infiltrates into the pancreatic islets (insulitis) progressing to diabetes. The NOD.ldd3/1 0/17/1 8/9(LD) congenic mouse, which has a 95% NOD genetic background and 5% "protective" B6/B10 genetic background, was bred from the NOD.ldd3/10/17/18 and NOD.ldd9 congenic mice, and is completely protected from autoimmune diabetes. However, we have discovered that it develops an entirely separate disease characterized by lymphocytic infiltrates into the portal tract, anti-pyruvate dehydrogenase complex (PDC) and other autoantibodies, and progressive polycystic liver leading to fatal biliary obstruction. In this grant, we will dissect the immunological, cellular, and genetic mechanisms of this novel disease. The central hypothesis of this grant is that the biliary disease in NOD.ldd3/10/17/18/9(LD) mice is an autoimmune disease arising via an interaction between the NOD background genes and B6/B10 loci, which are "protective" for autoimmune diabetes. This model provides a unique opportunity to dissect genetic and immunologic mechanisms resulting in 2 different organ specific autoimmune diseases in a genetically related pedigree. In specific aim one, we will define cellular and immunogenetic mechanisms of the liver disease in NOD.ldd3/10/17/18/9(LD) congenic mice by using transfer studies and related NOD congenic strains. In specific aim two, we will dissect cellular and immunogenetic mechanisms of immune subphenotypes in NOD.ldd3/10/17/18/9(LD) and related NOD congenic mice, including autoantibody production, T and B cell responses to PDC (Pyruvate dehydrogenase, specifically the E2 component), and mechanisms of lymphocytic liver infiltration in NOD.ldd3/10/17/18/9(LD) and related congenic mice. These studies are important for understanding the pathogenesis of autoimmune biliary diseases, autoimmune diabetes, and the genetics of autoimmunity in families.

描述（由申请人提供）：本提案的目的是确定在NOD.ldd3/10/17/18/9（LD）小鼠中发现的新型自身免疫性和胆道疾病的机制。非肥胖糖尿病（NOD）小鼠是自发的、遗传复杂的自身免疫性糖尿病的动物模型。NOD小鼠发生淋巴细胞浸润到胰岛中（胰岛炎），进展为糖尿病。NOD.ldd3/10/17/18/9（LD）同源小鼠，其具有95%NOD遗传背景和5%“保护性”B6/B10遗传背景，由NOD.ldd3/10/17/18和NOD.ldd9同源小鼠繁殖，并且完全免受自身免疫性糖尿病的影响。然而，我们发现它发展为一种完全独立的疾病，其特征为淋巴细胞浸润到门脉道，抗丙酮酸脱氢酶复合物（PDC）和其他自身抗体，以及导致致命性胆道梗阻的进行性多囊肝。在这项资助中，我们将剖析这种新疾病的免疫学、细胞学和遗传学机制。这项资助的中心假设是NOD.ldd3/10/17/18/9（LD）小鼠的胆道疾病是一种自身免疫性疾病，通过NOD背景基因和B6/B10位点之间的相互作用而产生，这对自身免疫性糖尿病具有“保护作用”。该模型提供了一个独特的机会，剖析遗传和免疫机制，导致2种不同的器官特异性自身免疫性疾病的遗传相关的谱系。在具体的目标之一，我们将确定NOD.ldd3/10/17/18/9（LD）同源小鼠的肝脏疾病的细胞和免疫遗传机制，通过使用转移研究和相关的NOD同源株。在具体的目标二，我们将解剖NOD.ldd3/10/17/18/9（LD）和相关的NOD同类小鼠的免疫亚表型的细胞和免疫遗传学机制，包括自身抗体的产生，T和B细胞对PDC（丙酮酸脱氢酶，特别是E2组分）的反应，以及NOD.ldd3/10/17/18/9（LD）和相关的同类小鼠的淋巴细胞肝浸润的机制。这些研究对于了解自身免疫性胆道疾病、自身免疫性糖尿病的发病机制以及家族中自身免疫的遗传学具有重要意义。