Assembly of disease-relevant pathways in the mouse

小鼠疾病相关通路的组装

基本信息

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
项目类别：
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&apos 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

项目摘要

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有关基因在规范生物学中的作用的重要信息疾病的发病机制和发病机制已被鉴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、心血管疾病和癌症包括复杂的模型。是特定近交系小鼠所特有的，例如糖尿病 NOD 小鼠系和模型通过操纵小鼠种系产生这些操纵包括引入转基因，通过定向诱变去除基因并将点突变引入小鼠基因。通常，模型的开发需要培育小鼠以产生携带多种基因的动物。虽然小鼠模型对于理解疾病的发病机制非常有用，在许多情况下，他们不适合新疗法的评估。开发中的治疗抗体与直系同源小鼠基因发生交叉反应，以及 Fc 的分布物种间受体的差异以及抗体清除率的差异使得评估这些药物变得困难。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用于研究此类疗法的功效。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并不与面临疾病风险的个体相似，也许更重要的是，这些模型不适合。随着影响疾病发病机制的新遗传因素的确定，进一步快速进行遗传操作。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在此应用中，我们建议制定策略。快速生成小鼠模型的方法和方法可用于：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）测试具体而言，我们建议开发针对这些疾病相关基因的疗法。鼠标线可用于此类评估 ¿ -分泌酶复合物。介导许多重要分子的膜内裂解，包括淀粉样前体蛋白 (APP) APP 的切割。 -分泌酶产量 ¿ -淀粉样蛋白，斑块特征的主要成分阿尔茨海默病。