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：
10928527
负责人：
Steven Holland
金额：
$ 108.65万
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/10928527
关键词：
Affect Alleles Aneurysm Animals Area B-Lymphocytes Biochemical Biological Bone Marrow Bone Marrow Transplantation Cardiovascular system Cells Chronic Granulomatous Disease Clinical Coccidioides Collaborations Cyst Defect Dental Diagnosis Disease Distant Dominant-Negative Mutation Endothelial Cells Enzymes Extramural Activities Functional disorder Generations Genes Genetic Genotype Genus staphylococcus Goals Hematopoietic Histopathology Histoplasma Human Hypersensitivity IL17 gene IgE Immune Impaired wound healing Impairment In Vitro Infection Inflammation Inflammatory Inflammatory Bowel Diseases Innate Immune Response Interferon Type II Intestines Investigation Job&apos s Syndrome Laboratories Link Lung Lymphopenia Malignant Neoplasms Metabolism Molecular Molecular Genetics Mus Muscle Cells Mutation Mycoses Myelogenous 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 Pathogenesis Pathogenicity Patients Peroxides Phagocytes Phenotype Portugal Predisposition Production Productivity Recurrence Reporting Research Personnel Resistance Respiratory Tract Infections Role STAT1 gene STAT3 gene Specimen Superoxides Syndrome T-Lymphocyte TNF gene Transgenic Animals Transplant-Related Disorder Vascular Endothelial Cell Work arterial tortuosity autosome chemokine cohort congenital immunodeficiency cytokine dominant genetic mutation gain of function gastrointestinal human model immune function immunopathology intercellular communication interest loss of function microbiome research mouse model programs rac2 GTP-binding protein recurrent infection

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. We have also defined the microbiomic aspects of CGD bowel disease, which are important in the induction of inflammation. 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 low in circulating 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. Further, the infections in these mice are driven in part by the proinflammatory molecule tumor necrosis factor, offering new avenues for therapy. 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 that de novo dominant mutations in the protein RAC2 can cause severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections. Dominant activating mutations were found in 3 patients. 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。我们还定义了CGD肠道疾病的微生物组方面，这对于诱导炎症很重要。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，这在Job综合征患者的循环细胞中较低。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。此外，这些小鼠的感染部分是由促炎分子肿瘤坏死因子驱动的，提供了新的治疗途径。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。在NCI研究人员的情况下，我们为Dock8缺乏症制定了一项全面而成功的骨髓移植计划。最近，我们确定蛋白质Rac2中的从头显性突变会引起严重的T-和B细胞淋巴细胞减少症，髓样功能障碍和复发性呼吸道感染。在3例患者中发现了主要的激活突变。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。

项目成果

期刊论文数量（132）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Anti-cytokine autoantibodies explain some chronic mucocutaneous candidiasis.

DOI：
10.1038/icb.2010.72
发表时间：
2010-08
期刊：
IMMUNOLOGY AND CELL BIOLOGY
影响因子：
4
作者：
Browne, Sarah K.;Holland, Steven M.
通讯作者：
Holland, Steven M.

Twenty-year follow-up of esophageal involvement in chronic granulomatous disease.

慢性肉芽肿病食管受累的二十年随访。

DOI：
10.1038/ajg.2009.274
发表时间：
2009
期刊：
The American journal of gastroenterology
影响因子：
0
作者：
Laskey,HeatherL;Gopal,Lakshmi;Gallin,JohnI;Holland,StevenM;Heller,Theo
通讯作者：
Heller,Theo

Pulmonary nontuberculous mycobacterial infections in hyper-IgE syndrome.

高 IgE 综合征中的肺部非结核分枝杆菌感染。

DOI：
10.1016/j.jaci.2009.07.007
发表时间：
2009
期刊：
The Journal of allergy and clinical immunology
影响因子：
0
作者：
Melia,Elizabeth;Freeman,AlexandraF;Shea,YvonneR;Hsu,AmyP;Holland,StevenM;Olivier,KennethN
通讯作者：
Olivier,KennethN

Spontaneous Staphylococcus xylosus Infection in Mice Deficient in NADPH Oxidase and Comparison with Other Laboratory Mouse Strains.

NADPH 氧化酶缺陷小鼠的自发木糖葡萄球菌感染以及与其他实验室小鼠品系的比较。

DOI：
发表时间：
2010
期刊：
Journal of the American Association for Laboratory Animal Science : JAALAS
影响因子：
0
作者：
Gozalo,AlfonsoS;Hoffmann,VictoriaJ;Brinster,LaurenR;Elkins,WilliamR;Ding,Li;Holland,StevenM
通讯作者：
Holland,StevenM

Bone density and fractures in autosomal dominant hyper IgE syndrome.

DOI：
10.1007/s10875-013-9982-2
发表时间：
2014-02
期刊：
Journal of clinical immunology
影响因子：
9.1
作者：
Sowerwine KJ;Shaw PA;Gu W;Ling JC;Collins MT;Darnell DN;Anderson VL;Davis J;Hsu A;Welch P;Puck JM;Holland SM;Freeman AF
通讯作者：
Freeman AF