Gene Targeted Mice with a Simplified Immune System

描述（由申请人提供）：基因靶向小鼠具有更简单的免疫系统。本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是由反转录因子组成的，其中许多是活跃的。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，Trex1缺陷患者和小鼠患有自身免疫性疾病。（ii）同样，积累内源性逆转录因子cDNA的整合酶抑制剂会加重小鼠狼疮和溶血性贫血。（iii）除了作为DNA突变子的功能外，AID还抑制LINE-1元件，并且aids缺陷患者会出现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。

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.