Mouse Model for Diseases of Protein Misfolding

蛋白质错误折叠疾病的小鼠模型

• 批准号: 8805919
• 负责人: P. MICHAEL CONN
• 金额: $ 3.87万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-07 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805919
• 关键词: Mouse; Model; Diseases; Protein; Misfolding

Project Summary/Abstract: This project is designed to develop and characterize two prototypic genetically modified mouse models for human diseases of protein folding. These models are required to bring a novel class of target-specific drugs, pharmacoperones, to human (and animal) use. Misfolded mutant proteins are detected by the cellular quality control system (QCS) and are typically retained in the endoplasmic reticulum (ER) for either reprocessing or degradation; frequently, these mutants result in disease. Studies in cell cultures indicate that these mutants can be rescued by target-specific small molecules (pharmacoperones) which enter cells, serve as templates that refold the mutants, and permit their passage to the plasma membrane. Many mutants retain or regain their fundamental properties as ion channels, enzymes or receptors when re-routed correctly. Diseases caused by misfolding (which may benefit from this approach) include cystic fibrosis, hypogonadotropic hypogonadism, nephrogenic diabetes insipidus, retinitis pigmentosa, hypercholesterolemia, cataracts, neurodegenerative diseases (Huntington's, Alzheimer's and Parkinson's), cancers and digestive disorders. It is fair to say that virtually every person will be affected by protein folding diseases during his or her lifetime, either directly or due to the illness of a loved one. In spite of this, there are few model systems, and none in small laboratory animals, that allow the translation of available in vitro data or the testing of "hits" from high throughput screening on protein rescue into in vivo systems. To date, therapeutic approaches in humans have relied on a small number of studies in end-of-life patients, using drugs that have never been fully characterized in animal models. Such models are needed to address drug safety, the pattern of drug administration required to optimize therapeutic effectiveness, and serve as a test model for new drugs in preclinical studies. The pattern (route, dose and frequency) is particularly important as the persistence of these drugs frequently inhibits the desired activity, once rescue has occurred, so they must be removed. Moreover a convenient laboratory model for these diseases is needed if the use of pharmacoperones is to translate to human well-being, since US law requires animal testing prior to normal human volunteers. The present study will characterize prototypic mouse models of misfolding, relying on an unusually well-characterized mutant of a physiologically important GPCR (i.e. the gonadotropin releasing hormone receptor). There is much information available on the mechanism of activation of the gonadotropin releasing hormone receptor (GnRHR) and on the biochemical mechanism by which the mutant E90K is believed to cause the disease state. This information has been helpful in guiding our choices of mutant E90K and will contribute to the success of this project. The two models to be used are available and have the predicted genotype and necessary phenotype.

项目概要/摘要： 该项目旨在开发和表征两种原型转基因小鼠模型， 蛋白质折叠的人类疾病这些模型需要带来一类新的靶向特异性药物， 药物操作素，用于人（和动物）使用。错误折叠的突变蛋白通过细胞质量检测 控制系统（QCS），通常保留在内质网（ER）中，用于再加工或 降解;这些突变体经常导致疾病。细胞培养的研究表明这些突变体 可以通过靶向特异性小分子（药物操作素）进入细胞，作为模板， 重新折叠突变体，并允许它们通过质膜。许多突变体保留或恢复了它们的 当正确地重新路由时，离子通道、酶或受体的基本特性。引起的疾病 错误折叠（可能受益于这种方法）包括囊性纤维化，低促性腺激素性性腺功能减退， 肾源性尿崩症、色素性视网膜炎、高胆固醇血症、白内障、神经变性 疾病（亨廷顿氏病、阿尔茨海默氏病和帕金森氏病）、癌症和消化系统疾病。可以说 事实上，每个人在其一生中都会受到蛋白质折叠疾病的影响，无论是直接还是由于 所爱之人的疾病尽管如此，目前的模型系统还很少，而且在小型实验室中还没有 动物，允许翻译可用的体外数据或测试来自高通量的“命中” 在体内系统中进行蛋白质拯救的筛选。迄今为止，人类的治疗方法依赖于一种 在临终患者中进行的少量研究，使用的药物从未在动物中得到充分表征 模型需要这种模式来解决药物安全性问题，优化药物管理模式， 治疗效果，并作为临床前研究中新药的测试模型。模式（路线， 剂量和频率）是特别重要的，因为这些药物的持久性经常抑制所需的 一旦发生救援行动，就必须将其清除。此外，一个方便的实验室模型， 如果药物的使用要转化为人类的福祉，这些疾病是需要的，因为美国法律 需要在正常人类志愿者之前进行动物试验。本研究将描述原型 错误折叠的小鼠模型，依赖于一个异常良好表征的生理学重要突变体， GPCR（即促性腺激素释放激素受体）。有很多关于 促性腺激素释放激素受体（GnRHR）的激活机制和生物化学 突变体E90 K被认为是导致疾病状态的机制。这些信息很有帮助 指导我们选择突变体E90 K，并将有助于该项目的成功。这两个模型是 所使用的基因是可用的，并且具有预测的基因型和必要的表型。