Gene Targeted Mice with a Simplified Immune System

具有简化免疫系统的基因靶向小鼠

• 批准号: 8088482
• 负责人: MATTHIAS R WABL
• 金额: $ 27.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-12 至 2011-07-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8088482
• 关键词: Applications Grants; Autoimmune Diseases; Autoimmune Hepatitis; Autoimmune Process; Autoimmunity; B-Cell Activation; B-Lymphocytes; Biological; Breeding; Categories; Cells; Chronic; Complementary DNA; Crohn' 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; Microbe; Modeling; Mouse Strains; 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

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。这项拨款申请旨在研究内源性逆转录酶对自身免疫性疾病的影响。我们的基因组几乎有一半是由逆转录酶组成的，其中许多是活性的。我们有三条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）Trex 1酶降解逆转录因子，Trex 1缺陷的患者和小鼠患有自身免疫性疾病。(ii)类似地，积累内源性逆转录因子cDNA的整合酶抑制剂加重小鼠的狼疮和溶血性贫血。(iii)除了其作为DNA突变体的功能外，AID还抑制LINE-1元件，并且AIDS缺陷患者发展出各种自身免疫性或炎性疾病。在这个方案中，我们将通过转基因来抑制逆转录因子的复制，并且携带转基因的小鼠应该没有或改善自身免疫性疾病。 公共卫生关系：免疫系统不仅可以应对来自外部世界的微生物的攻击，还可以对抗它所在的身体;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，首先是什么触发了自身免疫，仍然是一个谜。小鼠在心肌中积累了由身体自身基因组编码的寄生虫样DNA，就会患上心脏炎症。在其他小鼠中，不同的寄生虫元素可能导致溶血性贫血或狼疮。这项提案将测试许多寄生虫元素中的哪一个是导致自身免疫性疾病的原因，以及在这些寄生虫形成时摧毁它们或限制它们的增殖是否会预防这种疾病。