Transgenic Animal Models Of Human Immune Defects

人类免疫缺陷的转基因动物模型

基本信息

批准号：
9567417
负责人：
Steven Holland
金额：
$ 100.96万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
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/9567417
关键词：
Aneurysm Animal Model Animals Area Biochemical Bone Marrow Bone Marrow Transplantation Cardiovascular system Cells Child Chronic Granulomatous Disease Clinical Cyst Defect Dental Diagnosis Disease Distant Endothelial Cells Enzymes Extramural Activities Generations Genes Genetic Genotype Goals Hematopoietic Histopathology Human Hypersensitivity IgE Immune Impaired wound healing Impairment In Vitro Infection Inflammation Inflammatory Bowel Diseases Innate Immune Response Interleukin-17 Intestines Investigation Job&apos s Syndrome Laboratories Lead Link Lung Malignant Neoplasms Microbiology Molecular Molecular Genetics Mus Muscle Cells Mutation Mycoses NADPH Oxidase National Heart, Lung, and Blood Institute National Institute of Allergy and Infectious Disease National Institute of Arthritis and Musculoskeletal and Skin Diseases Natural Immunity Newly Diagnosed Occupations Operative Surgical Procedures Organism Osteopenia Pathogenicity Patients Phagocytes Phenotype Portugal Predisposition Production Recurrence Reporting Research Personnel Resistance Role STAT3 gene Scaffolding Protein Specimen Superoxides Syndrome Transgenic Animals Vascular Endothelial Cell chemokine cohort congenital immunodeficiency cytokine gastrointestinal immune function immunopathology intercellular communication interest mouse model novel programs

项目摘要

We seek to understand the role of phagocytes in immune function through examination of the consequences of immune defects. Our major focus is on chronic granulomatous disease (CGD), which is caused by defects in the enzyme NADPH oxidase. The NADPH oxidase is involved in the generation and control of inflammation, protection from infection, and cell-cell signaling. We have a comprehensive portfolio involving patients, animals, and laboratory specimens. We have continued our exploration of the gastrointestinal manifestations of CGD, since almost 50% of patients develop inflammatory bowel disease. We have characterized the gastrointestinal histopathology and the role of surgery in the world's largest cohort of cases. We have characterized the molecular and functional aspects of newly diagnosed cases of Granulibacter bethesdensis, including an isolate from Portugal, which appears to be more pathogenic both in human reports and in CGD mice. Identification of the genetic and cellular basis of hyper-IgE recurrent infection syndrome (HIES or Job's syndrome), an autosomal dominant disease characterized by extremely elevated IgE, recurrent sino-pulmonary infections, osteopenia, kyphoscoliosis, pulmonary cysts, and dental abnormalities, as being due to STAT3 has informed broad areas of investigation. With NIAID, NIAMS and extramural collaborators we have identified abnormalities in other cytokines downstream of STAT3, most notably IL-17, which is profoundly low in cells from Job's syndrome patients. Collaborating with investigators in NIAMS we have created a mouse model of STAT3 deficiency which has impaired wound healing and staphylococcal control. Collaborating with investigators in NHLBI we continue to study vascular endothelial cells from patients with STAT3 deficeincy in vitro, deriving endothelial and muscle cells from STAT3 deficient patients that have shown impaired chemokine production. With NCI investigators we have developed a comprehensive and successful bone marrow transplantation program for DOCK8 deficiency Recently we identified novel defects in the scaffolding protein WDR1/AIP1. Interestingly enough, we have found the same defect in children seen here over the last 25 years with identified mutations in the same gene. These combined approaches continue to be productive and help us understand innate immunity and inflammation. These studies will help us understand several different infections, including filamentous fungal infections, at a molecular genetic and functional level.

我们试图通过检查免疫缺陷的后果来了解吞噬细胞在免疫功能中的作用。我们的主要重点是慢性肉芽肿性疾病（CGD），这是由酶NADPH氧化酶缺陷引起的。 NADPH氧化酶参与炎症的产生和控制，免受感染的保护和细胞信号传导。我们有一个涉及患者，动物和实验室标本的全面投资组合。我们继续探索CGD的胃肠道表现，因为近50％的患者患有炎症性肠病。我们已经表征了胃肠道组织病理学和手术在世界上最大的病例中的作用。我们已经表征了新诊断的肉芽杆菌贝塞斯丁菌病例的分子和功能方面，其中包括来自葡萄牙的分离株，在人类报告和CGD小鼠中似乎更具致病性。鉴定超神经复发综合征（HIES或约伯综合征）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，复发性中性肺部感染，骨质减少症，骨s骨，kyphsoscoliosis，knephoscoliosis，knephsoscoliosis，knephsosis，肺部和牙科囊肿和牙齿替代领域，以及已及时的STAT3。使用NIAID，NIAMS和壁外合作者，我们已经确定了STAT3下游的其他细胞因子的异常，最著名的是IL-17，这对Job综合征患者的细胞非常低。与NIAMS的研究人员合作，我们创建了一个STAT3缺乏症的小鼠模型，该模型损害了伤口愈合和葡萄球菌控制。与NHLBI的研究人员合作，我们继续研究来自Stat3 Deficeincy体外患者的血管内皮细胞，从STAT3缺陷患者中得出内皮细胞和肌肉细胞，这些患者显示出趋化因子产生受损。与NCI调查人员一起，我们制定了一个全面而成功的骨髓移植计划，用于DOCK8缺乏症最近，我们确定了脚手架蛋白WDR1/AIP1中的新型缺陷。有趣的是，在过去25年中，我们发现在这里发现的儿童中存在相同的缺陷，并在同一基因中发现了突变。这些合并的方法继续提高生产力，并帮助我们了解先天的免疫力和炎症。这些研究将有助于我们了解几种不同的感染，包括分子遗传和功能水平，包括丝状真菌感染。