Role of PSTPIP1 in a Mouse Model of PAPA Syndrome

描述(申请人提供)：热原性关节炎，坏疽脓皮病和痤疮(PAPA)综合征，以前被称为条纹白细胞因子病，是一种罕见的常染色体显性自体炎症性疾病，特征是关节和皮肤无菌炎症、关节炎和严重痤疮。这种疾病与PSTPIP1基因的两个明确突变密切相关。相关的关节炎通常会导致关节破坏和虚弱。Papa综合征相关的坏疽脓皮病和痤疮对包括类固醇或大剂量抗生素在内的常规治疗都没有很好的反应，尽管现在有报道使用人白细胞介素1受体拮抗剂成功地治疗，这表明IL-1？体外研究表明，caspase-1激活炎性小体的失调可能参与了发病机制。突变体PSTPIP1被认为是自发的多聚体，随后与吡喃结合，并通过接头ASC激活caspase 1。然而，人们对PSTPIP1的正常生理功能以及突变的PSTPIP1蛋白如何引起炎症体激活知之甚少。为了阐明PSTPIP1的功能，我们在小鼠中建立了PSTPIP1编码基因的条件等位基因。PSTPIP1表达的消融可以以有条件的方式实现。利用这种条件基因敲除株，我们将在体内和体外测试PSTPIP1在炎症体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感染挑战，应该能阐明PSTPIP1的正常生理作用。此外，我们还产生了小鼠品系，在这些品系中，与人类突变相对应的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特异性的方式诱导。我们推测，突变的PSTPIP1的异位表达将导致这些小鼠出现Papa样疾病。通过分析转基因小鼠的表型，我们希望对突变的PSTPIP1如何导致Papa综合征有更深入的了解。此外，我们相信，拟议的研究将为自体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治疗方法提供新的线索。

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.