Murine Model of Job's syndrome

乔布氏综合症小鼠模型

基本信息

批准号：
8320852
负责人：
JOHN P MANIS
金额：
$ 20.58万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-17 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8320852
关键词：
Affect Alleles B-Cell Development B-Lymphocytes Bone Growth Breeding Candidiasis Cells Chronic Clinical DNA Binding Domain Defect Dentition Development Differentiation and Growth Disease Dominant-Negative Mutation ES Cell Line Eczema Face Functional disorder Gene Expression Profiling Gene Targeting Genes Genetic Genetic Recombination Glycoproteins IgE Immune Immune response Immune system Immunization Immunoglobulin Class Switching Immunoglobulin Switch Recombination Immunoglobulins Immunologic Deficiency Syndromes Immunologics In Vitro Inflammatory Response Inherited Job&apos s Syndrome Joints Lead Lesion Lung Lymphoma Mediating Modeling Monitor Mus Mutation Nature Pathway interactions Patients Penetrance Phenotype Point Mutation Predisposition Recurrence Reporter Reporting Role STAT3 gene Serum Signal Pathway Signal Transduction Signal Transduction Pathway Skin Source Staphylococcal Infections Stat3 protein Stem cells Structure Syndrome System T-Cell Development T-Lymphocyte T-Lymphocyte Subsets Testing Tissues Tooth structure Transactivation base body system bone cell growth cellular development congenital immunodeficiency cytokine disease phenotype embryonic stem cell human disease improved insight leukemia inhibitory factor mouse model mutant mutation carrier novel pluripotency progenitor promoter scoliosis self-renewal src Homology Domains therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Primary Immunodeficiencies (PID) commonly result from either an inherited block in cellular development of the immune system or in the inability of the immune system to properly regulate immune responses. In some specific diseases, developmental blocks are associated with both a precise immune defect and an altered inflammatory response (e.g. Omenn's syndrome). Patients with PID have been the source for numerous studies that resulted in significant insights into basic mechanisms of the immune system, and continue to offer unique investigative opportunities. The Hyper-IgE syndrome (HIES) is a primary immunodeficiency disorder generally characterized by chronic eczema, recurrent staphylococcal infections, and increased serum IgE levels. The autosomal dominant (AD) form (Job's syndrome) is additionally distinguished by multi-system manifestations including abnormal dentition, joint hyperextensibility, and a distinct facial structure. Most cases of Job's syndrome are sporadic in nature, however familial cases have also been reported. Recently, hypomorphic mutations in the Stat3 gene have been found to be a causative factor in Job's syndrome. Specifically, heterozygous, dominant-negative point mutations were found in distinct domains of the Stat3 gene including: the highly conserved DNA binding domain, the Src homology domain, and in the transactivation domain. While patients with Job's syndrome harbor mutations in Stat3, there still is no clear relationship between the exact genetic lesion and the phenotype of patients with HIES. In this proposal, we seek to generate murine models of Job's syndrome that accurately recapitulate the human disease in order to understand the basic mechanisms that lead to varied clinical manifestations

描述（由申请人提供）：原发性免疫缺陷（PID）通常是由于免疫系统细胞发育的遗传性障碍或免疫系统无法正确调节免疫反应造成的。在某些特定疾病中，发育障碍与精确的免疫缺陷和炎症反应改变有关（例如奥门综合征）。 PID 患者已成为众多研究的来源，这些研究对免疫系统的基本机制产生了重要的见解，并继续提供独特的研究机会。高 IgE 综合征 (HIES) 是一种原发性免疫缺陷性疾病，通常以慢性湿疹、复发性葡萄球菌感染和血清 IgE 水平升高为特征。常染色体显性遗传 (AD) 形式（乔布氏综合征）还具有多系统表现，包括牙列异常、关节过度伸展和独特的面部结构。大多数乔布氏综合症病例本质上是散发性的，但也有家族病例的报道。最近，Stat3基因的亚等位性突变被发现是乔布氏综合症的致病因素。具体来说，在 Stat3 基因的不同结构域中发现了杂合、显性失活点突变，包括：高度保守的 DNA 结合结构域、Src 同源结构域和反式激活结构域。虽然乔布斯综合征患者存在 Stat3 突变，但确切的基因损伤与 HIES 患者的表型之间仍然没有明确的关系。在本提案中，我们寻求生成乔布氏综合症的小鼠模型，准确地概括人类疾病，以了解导致不同临床表现的基本机制