Gene Targeted Mice with a Simplified Immune System

描述(申请人提供)：免疫系统更简单的基因靶向小鼠。这项拨款申请建议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是由逆转录元件组成的，其中许多都是活跃的。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)TREX1酶降解逆转录因子，而TREX1缺陷的患者和小鼠患有自身免疫性疾病。(Ii)类似地，积聚内源性逆转录素基因的整合酶抑制剂会加重小鼠的狼疮和溶血性贫血。(Iii)除了作为DNA突变子的功能外，AID还抑制LINE-1元件，AID缺陷的患者会发展成各种自身免疫性或炎症性疾病。在这个建议中，我们将通过转基因来抑制逆转录元件的复制，并且携带转基因的小鼠应该没有或改善了自身免疫性疾病。 与公共健康相关：免疫系统可能不会只应对来自外部世界的微生物的攻击，而是可能会针对它所在的身体；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，最初是什么触发了自身免疫，仍然是一个谜。在心肌中积累由人体自身基因组编码的类似寄生虫的DNA的小鼠，会患上心脏炎症。在其他小鼠中，不同的寄生虫成分可能与溶血性贫血或狼疮有关。这项提议将测试许多寄生虫中的哪些是自身免疫性疾病的罪魁祸首，以及在这些寄生虫形成时将其消灭或限制它们的扩散是否可以预防这种疾病。

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.