Role of PSTPIP1 in a Mouse Model of PAPA Syndrome

描述（由申请人提供）：热原性关节炎，坏疽性脓皮病和痤疮（PAPA）综合征，以前称为条纹白细胞因子病，是一种罕见的常染色体显性自身炎症疾病，其特征是关节和皮肤的无菌炎症，关节炎和严重痤疮。该疾病与PSTPIP1基因的两个明确突变密切相关。相关的关节炎常常导致关节破坏和衰弱。与PAPA综合征相关的坏疽性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疗效，尽管现在有报道称使用人类白细胞介素(IL)-1受体拮抗剂成功治疗，这表明IL-1受体拮抗剂可能起因果作用。体外研究表明，caspase-1激活炎性小体的失调可能与发病机制有关。突变体PSTPIP1自发聚合，随后结合PYRIN，并通过适配器ASC激活caspase 1。然而，人们对PSTPIP1的正常生理功能知之甚少，也不知道突变的PSTPIP1蛋白如何引起炎性小体激活。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表达的消融可以有条件地实现。利用这种条件敲除菌株，我们将在体内和体外测试PSTPIP1在炎性体激活过程中的重要性。生化研究以及来自这些小鼠的细胞或小鼠本身的感染挑战，应该揭示PSTPIP1的正常生理作用。此外，我们还利用Rosa 26基因座靶向技术，在小鼠品系中以组织或细胞系特异性的方式诱导了与人类突变相对应的PSTPIP1突变体的异位表达。我们假设突变体PSTPIP1的异位表达将导致这些小鼠出现papa样疾病。通过分析在转基因小鼠中产生的表型，我们期望深入了解突变PSTPIP1如何引起PAPA综合征。此外，我们相信我们提出的研究将为自身炎症疾病的病理生理过程提供见解，并为免疫疾病的治疗设计提供新的线索。

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.