Role of PSTPIP1 in a Mouse Model of PAPA Syndrome

PSTPIP1 在 PAPA 综合征小鼠模型中的作用

基本信息

批准号：
8176899
负责人：
Douglas T Golenbock
金额：
$ 24.68万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
2011-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8176899
关键词：
Ablation Acne Actins Acute suppurative arthritis due to bacteria Adaptor Signaling Protein Alleles Alzheimer&apos s Disease Antibiotics Arthritis Atherosclerosis Binding Biochemical Breeding Caspase-1 Cell Lineage Cells Code Cytoskeleton Development Disease Dose Drug Design Ectopic Expression Familial Mediterranean Fever Family member Fever Floods Genes Genetic Recombination Genetic Techniques Genetically Engineered Mouse Gout Hereditary Disease Human Immune System Diseases Immune response In Vitro Infection Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-18 Interleukins Intervention Joints Knock-out Knowledge Lead Leukocytes Light Link Mediating Molecular Mouse Strains Mus Mutant Strains Mice Mutation Names Pain Pathogenesis Pathology Pattern Phenotype Physiological Play Process Production Proline Protein Serine/Threonine Phosphatase Proteins Pyoderma Gangrenosum Receptor Gene Regulation Reporting Research Role Rosa Skin Sterility Steroids Syndrome Technology Testing Therapeutic Tissues Transgenic Mice Ursidae Family Viral Work anakinra conventional therapy cytokine in vivo insight joint destruction loss of function microbial mouse model mutant novel pathogen protein complex receptor response therapy design

项目摘要

DESCRIPTION (provided by applicant): Pyrogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, previously referred to as streaking leucocyte factor disease, is a rare autosomal dominant autoinflammatory disorder characterized by sterile inflammation of the joints and skin, arthritis and severe acne. The disease is strongly associated with two defined mutations in the PSTPIP1 gene. The associated arthritis often leads to joint destruction and debilitation. Neither PAPA syndrome related pyoderma gangrenosum nor acne respond well to conventional therapy, including steroids or high dose antibiotics, although there are now reports of successful therapy using human interleukin (IL)-1 receptor antagonist, suggesting a causal role for IL-1?. In vitro studies have shown that dysregulation of caspase-1 activating inflammasomes may contribute to the pathogenesis. It is thought that mutant PSTPIP1 multimerizes spontaneously, subsequently binds PYRIN, and activates caspase 1 via the adapter ASC. However, little is known about the normal physiological function of PSTPIP1 and nor how mutant PSTPIP1 proteins cause inflammasome activation. To elucidate the function of PSTPIP1, we have established a conditional allele of the Pstpip1 encoding gene in mice. Ablation of PSTPIP1 expression can be achieved in a conditional manner. Using this conditional knockout strain, we will test the importance of PSTPIP1 in the process of inflammasome activation both in vivo and in vitro. Biochemical studies as well as infectious challenges of cells derived from these mice, or the mice themselves, should shed light on the normal physiological role of PSTPIP1. In addition, we have also generated mouse strains in which ectopic expression of mutants of PSTPIP1 that correspond to the human mutations can be induced in a tissue or cell lineage specific manner using the Rosa 26 locus targeting technology. We hypothesize that ectopic expression of mutant PSTPIP1 will lead to PAPA-like disease conditions in these mice. By analyzing the resultant phenotypes in the transgenic mice, we expect to gain insights into how mutant PSTPIP1 causes PAPA syndrome. In addition, we believe the proposed research will provide insights into the pathophysiological processes of autoinflammatory diseases and lead to new clues in designing therapies for immune disorders. PUBLIC HEALTH RELEVANCE: Pyrogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is a rare genetic disease that causes severe inflammation in joints and skin. Mutations in the gene encoding a protein named PSTPIP1 cause the disease, although it is not known how. Using modern genetic techniques, we have established mouse models of the disease. Results from this research may lead to identification of novel targets for rational drug design to treat inflammatory diseases such arthritis.

描述（由申请人提供）：热电学关节炎，脓虫性腺坏疽和痤疮（PAPA）综合征，以前称为条纹白细胞因子疾病，是一种罕见的常染色体显性自染色体自身炎症性疾病，其特征是关节和皮肤，关节炎和关节炎和关节炎和关节炎和严重的痤疮的无菌炎症。该疾病与PSTPIP1基因中的两个定义突变密切相关。相关关节炎通常会导致关节破坏和衰弱。爸爸综合征与脓毒素相关的坏疽和痤疮对传统疗法的反应均未很好地反应，包括类固醇或高剂量抗生素，尽管现在有报道称使用人白介素（IL）-1受体拮抗剂成功治疗，这表明IL-1的因果关系作用。体外研究表明，caspase-1激活炎症的失调可能导致发病机理。人们认为，突变体PSTPIP1自发地进行了多重生产，随后结合吡啶，并通过适配器ASC激活caspase 1。然而，对PSTPIP1的正常生理功能以及突变体PSTPIP1蛋白如何引起炎症体激活知之甚少。为了阐明PSTPIP1的功能，我们已经建立了小鼠中PSTPIP1编码基因的条件等位基因。可以以条件方式实现PSTPIP1表达的消融。使用这种条件敲除菌株，我们将测试PSTPIP1在体内和体外激活过程中的重要性。生化研究以及来自这些小鼠或小鼠本身的细胞的传染性挑战，应阐明PSTPIP1的正常生理作用。此外，我们还产生了小鼠菌株，其中PSTPIP1突变体的异位表达可以使用ROSA 26基因座靶向技术以组织或细胞谱系的特定方式诱导与人类突变相对应的相对应。我们假设突变体PSTPIP1的异位表达将导致这些小鼠的爸爸样疾病。通过分析转基因小鼠中所得的表型，我们希望能够了解突变体PSTPIP1如何引起爸爸综合征。此外，我们认为拟议的研究将为自身炎症性疾病的病理生理过程提供见解，并为设计免疫疾病的疗法提供新的线索。公共卫生相关性：热产性关节炎，脓虫性腺坏疽和痤疮（爸爸）综合征是一种罕见的遗传疾病，会引起关节和皮肤的严重炎症。编码一个名为PSTPIP1的蛋白质的基因中的突变会导致该疾病，尽管尚不清楚。使用现代遗传技术，我们建立了该疾病的小鼠模型。这项研究的结果可能导致鉴定出理性药物设计的新靶标，以治疗这种关节炎。