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.

小鼠疾病相关通路的组装 小鼠继续提供重要的信息，基因的作用，在规范生物学 和发病机理。已经确定并开发了许多疾病的小鼠模型，包括 老年痴呆症，自身免疫性疾病，心血管疾病和癌症。其中包括复杂的模型 对于特定的近交系小鼠，例如糖尿病NOD小鼠系和已经被 通过操纵小鼠生殖细胞产生的。这些操作包括引入转基因， 通过靶向诱变去除基因并将点突变引入小鼠基因。 通常，模型的开发需要繁殖小鼠以产生携带多个基因的动物。 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，它们不适合于新疗法的评价。例如， 开发中的治疗性抗体与直系同源小鼠基因以及Fc的分布发生交叉反应 物种之间的受体和抗体清除率的差异使得这些药物的评价变得困难。 类似地，人和小鼠之间在小分子代谢方面的差异限制了药物的有用性。 许多小鼠疾病模型用于研究这类治疗剂的功效。更以 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 类似于有患病风险的个体。也许更重要的是，这些模型不适合 进一步的快速遗传操作作为影响疾病发病机理的新遗传因子被鉴定。在 此外，当发现新的疾病相关的多态性时，很少有模型允许容易的测试 这些变体的功能含义。在本申请中，我们提出了发展战略， 和用于快速产生小鼠模型的方法，所述小鼠模型可用于：1）疾病的功能评估 相关多态性，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剂。具体来说，我们建议开发细胞和 小鼠品系，用于这种评估的β-分泌酶复合物。这种多亚基蛋白酶复合体 介导包括淀粉样前体蛋白在内的许多重要分子的膜内裂解 （APP）。APP被<$-分泌酶切割产生<$-淀粉样蛋白，淀粉样蛋白是斑块的主要成分， 老年痴呆症