Murine Model of Job's syndrome

乔布氏综合症小鼠模型

• 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
• 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' 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

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阻滞或免疫系统无法正确调节免疫反应而引起的。在某些特定疾病中，发育障碍与精确的免疫缺陷和改变的炎症反应（例如Omenn综合征）有关。PID患者一直是众多研究的来源，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（AD）形式（乔布综合征）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。大多数约伯综合征病例在性质上是散发性的，但也有家族性病例的报道。最近，已发现Stat3基因的亚型突变是Job综合征的致病因素。具体而言，杂合，显性负性点突变被发现在不同的领域的Stat3基因，包括：高度保守的DNA结合结构域，Src同源结构域，并在反式激活结构域。虽然Job综合征患者在Stat3中存在突变，但确切的遗传病变与HIES患者的表型之间仍然没有明确的关系。在这个建议中，我们试图产生精确再现人类疾病的约伯综合征小鼠模型，以了解导致各种临床表现的基本机制