Functions of novel phospholipase D proteins in nucleic acid sensing

项目总结/摘要 这是一个R 01项目，研究磷脂酶D4（PLD 4）在核酸传感中的作用。白细胞 携带内吞DNA和RNA的保守传感器，这些传感器触发促炎性细胞因子的产生。 细胞因子，包括I型干扰素。随之而来的炎症可能有利于宿主防御， 微生物，病毒和肿瘤，但也可以是致病性的，并可能阻碍使用潜在的 治疗性寡核苷酸。PLD 4是一种溶酶体蛋白，其功能尚不清楚。全基因 相关研究已经将PLD 4与人类类风湿性关节炎和系统性硬化症联系起来。我们发现 PLD 4缺陷小鼠具有与人类疾病巨噬细胞活化综合征相似的表型， 其通过重复注射Toll样受体9激动剂在小鼠中模拟。在这里，我们测试 假设PLD 4分解摄入的DNA和RNA并调节宿主防御和炎症 通过促进破坏核酸和调节TLR 7、TLR 8（在人类中）和 TLR9。我们将描述PLD 4缺陷如何促进MAS样表型，以及PLD 4缺陷如何促进MAS样表型。 PLD 4或PLD 3 + PLD 4影响TLR 7和TLR 9对特异性配体的应答，导致细胞因子改变 分泌物还将评估PLD 4在自我/非自我辨别中的可能作用。远景目标 这些研究的目的是了解PLD 4的基本生物学，它在宿主防御和炎症中的功能， 并为未来潜在的转化研究奠定基础。

Project Summary/Abstract This is a R01 project to study the role of Phospholipase D4 (PLD4) in nucleic acid sensing. Leukocytes carry conserved sensors for endocytosed DNA and RNA that trigger the production of proinflammatory cytokines, including type I interferon. The ensuing inflammation can be beneficial for host defense to microorganisms, viruses, and tumors, but can also be pathogenic, and may thwart the use of potentially therapeutic oligonucleotides. PLD4 is a lysosomal protein whose function is not understood. Genome-wide association studies have linked PLD4 to human rheumatoid arthritis and systemic sclerosis. We find that PLD4-deficient mice have a phenotype similar to the human disease macrophage activation syndrome, which is mimicked in mice by repeated injections with Toll-like receptor 9 agonists. Here we test the hypotheses that PLD4 breaks down ingested DNA and RNA and regulates host defense and inflammation by promoting the destruction nucleic acids and regulating recognition by TLR7, TLR8 (in humans) and TLR9. We will characterize how PLD4 deficiency promotes a MAS-like phenotype and how deficiencies in PLD4 or PLD3+PLD4 affect TLR7 and TLR9 responses to specific ligands, leading to altered cytokine secretion. The possible role of PLD4 in self/nonself discrimination will also be assessed. The long-term goal of these studies is to understand the basic biology of PLD4, its functions in host defense and inflammation, and to develop a basis for potential future translational research.