Transgenic Animal Models Of Human Immune Defects

人类免疫缺陷的转基因动物模型

• 批准号: 6663610
• 负责人: Steven M Holland
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6663610
• 关键词: NAD(P)H dehydrogenase; adolescence (12-20); child (0-11); chronic granulomatous disease; enzyme activity; gene therapy; genetically modified animals; human subject; hyperglobulinemia; laboratory mouse; model design /development; molecular pathology; nonhuman therapy evaluation; pathologic process; patient oriented research

We seek to understand the role of enzyme systems in host immune defense, specifically the NADPH oxidase. We study the NADPH oxidase in the generation and control of inflammation, its role in protection from infection, and its role in how cells signal to each other. These are important issues to understand in order to better appreciate how to manipulate the immune system pharmacologically, immunologically, and genetically. We actively pursue a mixed approach to these issues by studying patients, animals, and laboratory specimens. We follow a large number of patients with NADPH oxidase deficiency, chronic granulomatous disease (CGD), and we have been involved in characterizing the infections and complications that they develop. We have also used a mouse created in my laboratory that is deficient in the NADPH oxidase and therefore closely mimics human CGD. Numerous studies in these mice have shown a critical role for this enzyme system in not only protection from infection but also in the magnitude and character of the inflammatory response. This mixed approach to understanding the NADPH oxidase in CGD has been very informative about the role of the innate immune system in both early and late aspects of the inflammatory response. We are also pursuing the genetic and cellular basis of another complex host defense defect, hyper-IgE and recurrent infection syndrome (Job's syndrome or HIE), an autosomal dominant disease characterized by extremely elevated IgE, recurrent sino- pulmonary infections, osteopenia, kyphoscoliosis, pulmonary cysts, and dental abnormalities. The gene(s) involved in Job's must be critically important to innate immunity, the early and late host immune responses, skeletal growth and development, and tooth deciduation. We have developed a comprehensive patient evaluation system and are now in the process of examining the data from over 90 candidate families. In the course of these studies we have identified novel phenocopies of Job's syndrome that are transmitted in a recessive pattern. The search for the genes responsible for these syndromes continues and will eventually lead to pathways that we can disrupt in mice to perform functional studies.

我们试图了解酶系统在宿主免疫防御中的作用，特别是NADPH氧化酶。我们研究了NADPH氧化酶在炎症的产生和控制中，其在防护中的作用以及其在细胞彼此信号方面的作用。这些是要理解的重要问题，以便更好地理解如何在药理，免疫学和遗传上操纵免疫系统。我们通过研究患者，动物和实验室标本来积极采用这些问题的混合方法。我们跟随大量患有NADPH氧化酶缺乏症，慢性肉芽肿性疾病（CGD）的患者，我们参与了表征其发展的感染和并发症。我们还使用了在我的实验室中创建的小鼠，该小鼠缺乏NADPH氧化酶，因此密切模仿了人CGD。这些小鼠的大量研究表明，该酶系统不仅可以保护感染，而且在炎症反应的大小和特征方面发挥了关键作用。理解CGD中NADPH氧化酶的这种混合方法对先天免疫系统在炎症反应的早期和晚期方面的作用非常有用。我们还追求另一种复杂的宿主防御缺陷，超生和复发性感染综合征（Job's综合征或HIE）的遗传和细胞基础，这是一种常染色体显性疾病，其特征是IGE极高的IGE，经常性中性肺部感染，骨质骨质疾病，骨科学，肺炎，肺部囊肿和dernormentis和dertal as dentrasmanties。参与约伯的基因对于先天免疫，早期和晚期的免疫反应，骨骼生长和发育以及牙齿固定至关重要。我们已经开发了一个全面的患者评估系统，现在正在检查90多个候选家庭的数据。在这些研究的过程中，我们已经确定了以隐性模式传播的乔布综合征的新型表现。寻找负责这些综合征的基因的搜索仍在继续，最终将导致我们可以在小鼠中破坏进行功能研究的途径。