Assembly of disease-relevant pathways in the mouse

描述（由申请人提供）：在小鼠中组装疾病相关通路小鼠继续提供有关基因在规范生物学和疾病发病机制中的作用的重要信息。小鼠模型已经被确定并开发用于许多疾病，包括阿尔茨海默病、自身免疫性疾病、心血管疾病和癌症。这些包括特定近交系小鼠特有的复杂模型，如糖尿病NOD小鼠系和通过操纵小鼠生殖系产生的模型。这些操作包括引入转基因、去除基因和通过靶向诱变将点突变引入小鼠基因。通常，模型的开发需要繁殖携带多种突变的小鼠。虽然小鼠模型在了解疾病的发病机制方面非常有用，但在许多情况下，它们不适用于新疗法的评估。例如，正在开发的治疗性抗体很少与同源小鼠基因交叉反应，Fc受体在物种之间的分布和抗体清除率的差异使这些药物的评价变得困难。同样，人类和小鼠在小分子代谢方面的差异限制了许多小鼠疾病模型对这类治疗药物疗效研究的有用性。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与具有疾病风险的个体的遗传结构并不相似。也许更重要的是，随着新的影响疾病发病机制的遗传因素被确定，这些模型不适合进一步的快速遗传操作。此外，当发现新的疾病相关多态性时，很少有模型可以轻松测试这些变异的功能含义。在此应用中，我们提出了快速生成小鼠模型的策略和方法，这些模型可用于：1)疾病相关多态性的功能评估，2)疾病发病机制中基因-基因相互作用的研究，以及3)针对这些疾病相关基因的治疗方法的测试。具体来说，我们建议开发细胞和小鼠系，用于这种评估-分泌酶复合物。这种多亚基蛋白酶复合物介导许多重要分子的膜内裂解，包括淀粉样蛋白前体蛋白（APP）。分泌酶裂解APP产生淀粉样蛋白，淀粉样蛋白是阿尔茨海默病斑块的主要成分。

DESCRIPTION (provided by applicant): 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.