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.

项目摘要/摘要： 该项目旨在开发和表征两个原型遗传修饰的鼠标模型 蛋白质折叠的人类疾病。这些模型需要带来一类新型靶标药物， 药物的使用，用于人类（和动物）的使用。通过细胞质量检测到错误折叠的突变蛋白 控制系统（QC），通常保留在内质网（ER）中，用于重新处理或 降解;这些突变体经常会导致疾病。细胞培养的研究表明这些突变体 可以通过进入细胞的靶标特异性小分子（Pharmacoperones）来挽救，作为模板 这会重新折叠突变体，并允许它们通过质膜。许多突变体保留或恢复 重新穿孔时，基本特性作为离子通道，酶或受体。引起的疾病 错误折叠（可能会从这种方法中受益）包括囊性纤维化，性腺功能低下， 肾脏发质糖尿病，色素性视网膜炎，高胆固醇血症，白内障，神经退行性 疾病（亨廷顿，阿尔茨海默氏症和帕金森氏症），癌症和消化系统疾病。可以公平地说 实际上，每个人都会直接或直接受到蛋白质折叠疾病的影响 亲人的病。尽管如此，小型实验室中的模型系统很少，没有 动物，可以翻译可用的体外数据或高吞吐量的“命中”的动物 筛选蛋白质营救到体内系统中。迄今为止，人类的治疗方法依赖 使用从未在动物中完全表征的药物，在寿命末患者中的少量研究 型号。需要这样的模型来解决药物安全，这是优化药物管理的模式 治疗有效性，并作为临床前研究中新药的测试模型。图案（路线， 剂量和频率）尤其重要，因为这些药物的持久性经常抑制所需的 活动，一旦发生救援，就必须将其删除。此外，方便的实验室模型 如果使用药甲酮是将人类的福祉转化为人类，则需要这些疾病 需要在正常人类志愿者之前进行动物测试。本研究将表征原型 鼠标折叠式错误模型，依赖于特征良好的生理上重要的突变体 GPCR（即促性腺激素释放激素受体）。关于 促性腺激素释放激素受体（GNRHR）的激活机理和生化的机理 人们认为突变体E90K引起疾病状态的机制。这些信息很有帮助 在指导我们对突变E90K的选择，并将为该项目的成功做出贡献。这两个模型是 使用可用，并具有预测的基因型和必要的表型。