Assembly of disease-relevant pathways in the mouse

小鼠疾病相关通路的组装

• 批准号: 8638644
• 负责人: Beverly H Koller
• 金额: $ 22.8万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638644
• 关键词: Alleles; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein Precursor; Animal Model; Animals; Antibodies; Architecture; Autoimmune Diseases; Biological Models; Biology; Breeding; CD44 gene; Cardiovascular Diseases; Caring; Cause of Death; Cell Line; Cell model; Cells; Characteristics; Chromosomes, Human, Pair 21; Complex; Dementia; Development; Disease; Disease model; Drug Evaluation; ES Cell Line; Elderly; Enhancers; Evaluation; Excision; Fc Receptor; Gene Targeting; Generations; Genes; Genetic; Genetic Polymorphism; Goals; Human; Impact evaluation; In Vitro; Inbred Mouse; Inbred NOD Mice; Individual; Malignant Neoplasms; Mediating; Metabolism; Modeling; Mouse Cell Line; Mouse Protein; Mus; Mutagenesis; Mutation; Neurons; Pathogenesis; Pathway interactions; Peptide Hydrolases; Persons; Point Mutation; Proteins; Reagent; Role; Series; Signaling Molecule; Source; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic antibodies; Transgenes; Variant; base; diabetic; disorder risk; embryonic stem cell; gene interaction; genetic manipulation; genetic variant; model development; mouse genome; mouse model; nicastrin protein; notch protein; novel; novel therapeutics; payment; peptide A; presenilin; protein distribution; public health relevance; rapid technique; secretase; small molecule; species difference; translational study; vector

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.

小鼠中疾病相关途径的组装 小鼠继续提供有关基因在两种正常生物学中的作用的重要信息 和疾病的发病机理。鼠标模型已被确定和开发针对许多疾病，包括 阿尔茨海默氏症，自身免疫性疾病，心血管疾病和癌症。这些包括复杂的模型 特定的近交小鼠系所独有的独特 通过操纵小鼠种系产生。这些操作包括引入翻译， 通过靶向诱变的去除基因和将点突变引入小鼠基因。 通常，模型的发展需要小鼠的繁殖才能产生携带多种的动物 突变。尽管小鼠模型在理解疾病的发病机理方面非常有用，但 在许多情况下，它们不适合评估新的治疗剂。例如，很少 发育交叉中的治疗性抗体与直系同源小鼠基因反应，FC的分布 物种之间的受体和抗体清除差异使这些药物的评估变得困难。 同样，小分子代谢中人与小鼠之间的差异限制了 许多小鼠疾病模型用于研究此类治疗的效率。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都没有 类似于有疾病风险的人。也许更重要的是，模型不适合 由于发现了影响疾病发病机理的新遗传因素，因此进一步快速的遗​​传操作。在 此外，当发现新型疾病相关的多态性时，很少有模型可以轻松测试 这些变体的功能含义。在此应用中，我们建议制定策略 和快速生成小鼠模型的方法有用：1）疾病的功能评估 相关的多态性，2）研究疾病发病机理中基因 - 基因相互作用的研究，3）测试 针对这些疾病相关基因的治疗。具体而言，我们建议开发细胞和 小鼠线可用于评估 - 分泌酶复合物。这种多生成蛋白酶复合物 介导许多重要分子（包括淀粉样蛋白前体蛋白）的膜内切割 （应用程序）。通过�-分泌酶对应用的裂解产生�-淀粉样蛋白，斑块特征的主要成分 阿尔茨海默氏病。