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。我们的主要关注点是慢性肉芽肿病 (CGD)，它是由 NADPH 氧化酶缺陷引起的。 NADPH 氧化酶参与炎症的产生和控制、感染保护以及细胞间信号传导。我们拥有涉及患者、动物和实验室标本的全面产品组合。我们继续探索 CGD 的胃肠道表现，因为近 50% 的患者会出现炎症性肠病。我们在世界上最大的病例群中描述了胃肠道组织病理学和手术的作用。我们对新诊断的 Bethesdensis 颗粒杆菌病例的分子和功能特征进行了表征，其中包括来自葡萄牙的分离株，该菌株在人类报告和 CGD 小鼠中似乎都更具致病性。我们还定义了 CGD 肠道疾病的微生物组学方面，这对于炎症的诱发很重要。鉴定高 IgE 复发性感染综合征（HIES 或乔布氏综合征）的遗传和细胞基础，这是一种常染色体显性遗传疾病，其特征是 IgE 极度升高、反复性肺部感染、骨质减少、脊柱后侧凸、肺囊肿和牙齿异常。由于 STAT3 已为广泛的调查领域提供了信息。通过 NIAID、NIAMS 和校外合作者，我们发现了 STAT3 下游其他细胞因子的异常，最明显的是 IL-17，它在乔布斯综合征患者的循环细胞中含量较低。我们与 NIAMS 的研究人员合作，创建了 STAT3 缺陷小鼠模型，该模型会损害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，这为治疗提供了新的途径。我们与 NHLBI 的研究人员合作，继续在体外研究来自 STAT3 缺陷患者的血管内皮细胞，从趋化因子产生受损的 STAT3 缺陷患者中衍生出内皮细胞和肌肉细胞。我们与 NCI 研究人员一起开发了针对 DOCK8 缺陷的全面且成功的骨髓移植计划。最近，我们发现 RAC2 蛋白的从头显性突变可导致严重的 T 细胞和 B 细胞淋巴细胞减少、骨髓功能障碍和反复呼吸道感染。在 3 名患者中发现显性激活突变。这些组合方法仍然富有成效，有助于我们了解先天免疫和炎症。这些研究将帮助我们在分子遗传和功能水平上了解几种不同的感染，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）

Complex regulation of human cathelicidin gene expression: novel splice variants and 5'UTR negative regulatory element.

人导管素基因表达的复杂调控：新型剪接变体和 5UTR 负调控元件。

DOI：
发表时间：
2008-01
期刊：
影响因子：
3.6
作者：
Elloumi, Houda Zghal;Holland, Steven M
通讯作者：
Holland, Steven M

Chronic granulomatous disease.

慢性肉芽肿病。

DOI：
发表时间：
2010-02
期刊：
影响因子：
9.1
作者：
Holland; Steven M
通讯作者：
Steven M

When to leave a stone unturned ...

什么时候要不遗余力......

DOI：
发表时间：
2010-08
期刊：
影响因子：
24.5
作者：
von Rosenvinge, Erik C;Koh, Christopher;Holland, Steven M;Heller, Theo
通讯作者：
Heller, Theo

Human leukocytes kill Aspergillus nidulans by reactive oxygen species-independent mechanisms.

人类白细胞通过活性氧独立机制杀死构巢曲霉。

DOI：
发表时间：
2011-02
期刊：
影响因子：
3.1
作者：
Henriet, Stefanie S V;Hermans, Peter W M;Verweij, Paul E;Simonetti, Elles;Holland, Steven M;Sugui, Janyce A;Kwon;Warris, Adilia
通讯作者：
Warris, Adilia

Corticosteroid therapy for liver abscess in chronic granulomatous disease.

皮质类固醇治疗慢性肉芽肿性疾病的肝脓肿。

DOI：
发表时间：
2012-03-01
期刊：
影响因子：
0
作者：
Leiding, Jennifer W;Freeman, Alexandra F;Marciano, Beatriz E;Anderson, Victoria L;Uzel, Gulbu;Malech, Harry L;DeRavin, SukSee;Wilks, David;Venkatesan, Aradhana M;Zerbe, Christa S;Heller, Theo;Holland, Steven M
通讯作者：
Holland, Steven M