Assembly of disease-relevant pathways in the mouse

小鼠体内疾病相关通路的组装 老鼠继续提供有关基因在两种标准生物学中的作用的重要信息 以及疾病的发病机制。已经为许多疾病识别和开发了小鼠模型，包括 阿尔茨海默氏症、自身免疫性疾病、心血管疾病和癌症。其中包括复杂的模型 独有的特定近交系小鼠，如糖尿病NOD小鼠系和已被 通过操纵小鼠生殖系产生的。这些操作包括引入转基因， 通过定向突变去除基因并将点突变引入小鼠基因。 通常，模型的开发需要饲养小鼠来产生携带多发性骨髓瘤的动物 突变。虽然小鼠模型在理解疾病的发病机制方面非常有用， 在许多情况下，他们不愿接受新疗法的评估。例如，很少有 正在开发的治疗性抗体与同源小鼠基因发生交叉反应，Fc的分布 不同物种之间的受体和抗体清除的差异使得对这些药物的评估变得困难。 同样，人类和小鼠在小分子新陈代谢方面的差异限制了 许多小鼠疾病模型用于研究这类疗法的疗效。此外，在 大多数情况下，迄今为止开发的大多数小鼠疾病模型的遗传结构不是 与处于疾病风险中的个体相似。或许更重要的是，这些模型并不服从于 进一步发现，快速基因操作是影响疾病发病机制的新的遗传因素。在……里面 此外，当发现新的与疾病相关的多态时，很少有模型允许轻松测试 这些变种的功能含义。在这一应用中，我们提出了发展战略 以及用于快速生成可用于：1)疾病的功能评估的小鼠模型的方法 相关的多态，2)疾病发病机制中基因-基因相互作用的研究，以及3)检测 针对这些疾病相关基因的治疗。具体地说，我们建议发展细胞和 对这种分泌酶复合体的评估有用的小鼠品系。这种多亚单位的蛋白水解酶复合体 介导包括淀粉样前体蛋白在内的许多重要分子的膜内切割 (应用程序)。APP被分泌酶切割产生淀粉样蛋白，这是斑块的主要成分 阿尔茨海默氏症。

Assembly of disease-relevant pathways in the mouse The mouse continues to provide important information concerning the role of genes in both normative biology and pathogenesis of disease. Mouse models have been identified and developed for many diseases, including Alzheimer's, autoimmune diseases, cardiovascular diseases and cancer. These include complex models unique to specific inbred mouse lines such as the diabetic NOD mouse line and models that have been generated by manipulation of the mouse germline. These manipulations include the introduction of transgenes, the removal of genes and the introduction of point mutations into mouse genes by targeted mutagenesis. Often, the development of models requires the breeding of mice to generate animals carrying multiple mutations. While mouse models have been enormously useful in understanding the pathogenesis of disease, in many cases they are not amenable to the evaluation of new therapeutics. For example, few of the therapeutic antibodies in development cross react with the orthologous mouse gene, and the distribution of Fc receptors between species and differences in antibody clearance makes evaluation of these drugs difficult. Similarly, differences between human and mouse in the metabolism of small molecules limit the usefulness of many mouse disease models for the study of the efficacy of this class of therapeutics. Furthermore, in the majority of cases, the genetic architecture of most mouse disease models developed to date does not resemble that of individuals at risk for disease. Perhaps more importantly, the models are not amenable to further rapid genetic manipulation as new genetic factors influencing disease pathogenesis are identified. In addition, when novel disease associated polymorphisms are discovered, few of the models allow easy testing of the functional implications of these variants. In this application we propose the development of strategies and methods for the rapid generation of mouse models useful for: 1) the functional evaluation of disease associated polymorphisms, 2) the study of gene-gene interactions in disease pathogenesis, and 3) testing of therapeutics directed against these disease associated genes. Specifically we propose to develop cell and mouse lines useful for such evaluation of the ¿-secretase complex. This multi-subunit protease complex mediates intramembranous cleavage of a number of important molecules including amyloid precursor protein (APP). Cleavage of APP by ¿-secretase yields ¿-amyloid, a primary component of plaques characteristic of Alzheimer's disease.