Gene Targeted Mice with a Simplified Immune System

具有简化免疫系统的基因靶向小鼠

基本信息

批准号：
8278599
负责人：
MATTHIAS R WABL
金额：
$ 38.24万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-04-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8278599
关键词：
Applications Grants Autoimmune Diseases Autoimmune Hepatitis Autoimmune Process Autoimmunity B-Cell Activation B-Lymphocytes Beryllium Biological Breeding Categories Cells Chronic Complementary DNA Crohn&apos s disease DNA Defense Mechanisms Diabetes Mellitus Disease Elements Enzymes Etiology Failure Family Family member Gene Targeting Gene Transfer Techniques Genes Genetic Recombination Genome Grant Heart Hemolytic Anemia Human Immune Immune system Immunoglobulin Switch Recombination Immunoglobulins Inbred NZB Mice Individual Inflammation Inflammatory Integrase Inhibitors Interferon Type I Knockout Mice Lead Left Lupus Mediating Messenger RNA Microbe Modeling Murine leukemia virus Mus Myocarditis Myocardium NZW Mouse Nuclear Nucleic Acids Parasites Patients Polyarthritides Proteins RNA Retroelements Retrotransposition Retrotransposon Retroviridae Role Site Syndrome Testing Thrombocytopenia Transcript Transgenes Transgenic Mice Transgenic Organisms Uveitis Viral activation-induced cytidine deaminase autoimmune gastritis exodeoxyribonuclease member prevent public health relevance research study response superinfection

项目摘要

DESCRIPTION (provided by applicant): Gene targeted mice with a simpler immune system. This grant application proposes to investigate the influence of endogenous retroelements on autoimmune disease. Almost half of our genome consists of retroelements-many of them active. We have three lines of evidence for our hypothesis that retroelements can mediate autoimmune disease: (i) The enzyme Trex1 degrades retroelements, and Trex1-deficient patients and mice suffer from autoimmune disease. (ii) Similarly, an integrase inhibitor that accumulates endogenous retroelement cDNA exacerbates lupus and hemolytic anemia in mice. (iii) Apart from its function as a DNA mutator, AID inhibits LINE-1 elements, and AID-deficient patients develop a variety of autoimmune or inflammatory disorders. In this proposal, we will inhibit retroelement replication by transgenesis, and the mice carrying the transgenes ought to have no or ameliorated autoimmune disease. PUBLIC HEALTH RELEVANCE: Instead of dealing only with attacks from microbes from the outside world, the immune system may turn against the very body of which it is a part; when this happens, a so-called autoimmune disease may result. What triggers autoimmunity in the first place, however, has remained a mystery. Mice that accumulate parasite-like DNA, encoded by the body's own genome, in the heart muscle suffer from inflammation of the heart. In other mice, different parasitic elements may be responsible for hemolytic anemia or lupus. This proposal will test which of the many parasitic elements are responsible for autoimmune disease, and whether destroying these parasites as they are formed, or limiting their proliferation, will prevent the disease.

描述（由申请人提供）：具有更简单免疫系统的基因靶向小鼠。该拨款申请旨在研究内源性逆转录因子对自身免疫性疾病的影响。我们的基因组几乎有一半由逆转录因子组成——其中许多是活跃的。我们有三个证据支持我们的假设，即逆转录因子可以介导自身免疫性疾病：（i）Trex1 酶降解逆转录因子，并且 Trex1 缺陷的患者和小鼠患有自身免疫性疾病。 (ii) 同样，积累内源性逆转录元件 cDNA 的整合酶抑制剂会加剧小鼠的狼疮和溶血性贫血。 (iii) 除了作为 DNA 突变体的功能外，AID 还抑制 LINE-1 元件，AID 缺陷的患者会出现多种自身免疫或炎症性疾病。在这个提议中，我们将通过转基因抑制逆转录元件复制，并且携带转基因的小鼠应该没有或改善自身免疫性疾病。公共卫生相关性：免疫系统不仅可以应对来自外界微生物的攻击，还可能会针对其所属的身体进行攻击；当这种情况发生时，可能会导致所谓的自身免疫性疾病。然而，到底是什么引发了自身免疫仍然是一个谜。在心肌中积累由人体自身基因组编码的寄生虫样 DNA 的小鼠会出现心脏炎症。在其他小鼠中，不同的寄生因素可能导致溶血性贫血或狼疮。该提案将测试众多寄生因素中哪些是导致自身免疫性疾病的原因，以及在这些寄生虫形成时将其消灭或限制其增殖是否可以预防这种疾病。