Murine Model of Job's syndrome

描述（由申请人提供）：原发性免疫缺陷（PID）通常由免疫系统细胞发育的遗传障碍或免疫系统无法适当调节免疫反应引起。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（如Omenn综合征）有关。PID患者已经成为许多研究的来源，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。常染色体显性显性（AD）形式（Job’s综合征）的另一个特点是多系统表现，包括牙列异常、关节过度伸展和明显的面部结构。大多数约伯氏综合征的病例是散发的，但也有家族性病例的报道。最近，Stat3基因的亚型突变被发现是导致Job’s综合征的一个因素。具体来说，在Stat3基因的不同区域发现了杂合子、显性负性点突变，包括高度保守的DNA结合区域、Src同源区域和反活化区域。虽然Job’s综合征患者的Stat3基因存在突变，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。在这一建议中，我们试图建立准确概括人类疾病的约伯氏综合征小鼠模型，以了解导致不同临床表现的基本机制

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