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：
8837717
负责人：
Beverly H Koller
金额：
$ 18.62万
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 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8837717
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 Genetic study Goals Health 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 rapid technique secretase small molecule species difference translational study vector

项目摘要

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.

描述（由申请人提供）：小鼠中疾病相关通路的组装小鼠继续提供有关基因在疾病的规范生物学和发病机制中的作用的重要信息已经鉴定和开发了许多疾病（包括阿尔茨海默病）的小鼠模型。、自身免疫性疾病、心血管疾病和癌症。这些复杂的模型是特定近交系小鼠所特有的，例如糖尿病 NOD 小鼠系和通过操作小鼠种系产生的模型。通常，模型的开发需要培育携带多种突变的动物，而小鼠模型对于了解疾病的发病机制非常有用。，在许多情况下，它们不适合新抗体疗法的评估，例如，开发中的治疗性抗体很少与直系同源小鼠基因发生交叉反应，并且 Fc 受体在物种之间的分布和清除率的差异使得这些评估成为可能。药物困难。类似地，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在研究此类疗法的功效方面的用途。此外，在大多数情况下，大多数小鼠疾病模型的遗传结构都是发达的。也许更重要的是，随着影响疾病发病机制的新遗传因素被发现，这些模型并不适合进一步的快速遗传操作。此外，当发现新的与疾病相关的多态性时，很少有这种模型。这些模型可以轻松测试功能含义在本申请中，我们提出了快速生成小鼠模型的策略和方法，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）具体来说，我们建议开发可用于此类评估的细胞和小鼠系。 -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，包括淀粉样前体蛋白 (APP)。 -分泌酶产量 ¿ -淀粉样蛋白，阿尔茨海默病斑块的主要成分。