Mechanism of Progranulin-mediated control of septic inflammation via IL-10

描述（由申请人提供）：前颗粒蛋白（PGRN）是一种在哺乳动物组织中广泛表达的细胞因子。PGRN在胚胎发育、性别分化、肿瘤发生、糖代谢和肥胖、免疫、感染和炎症等方面发挥重要作用。PGRN生成/功能的改变与创伤、感染、恶性肿瘤、损伤、神经退行性疾病（如阿尔茨海默病、多发性硬化症和系统性红斑狼疮）有关。PGRN如何调节这些生物过程尚不清楚。我们建议的主要假设是PGRN通过调节IL-10产生的能力在很大程度上控制全身性炎症和组织稳定性。具体来说，我们认为这一重要的调控途径按以下顺序分层结构：CCAAT/增强子结合蛋白（C/EBP）和IL-10。为了验证这一假设，我们将研究转录调节因子C/EBP？PGRN通过TNF受体介导的信号传导在分子水平上刺激IL-10基因的表达。然后，我们将通过C/EBPa阐明pgrn调节全身炎症反应的机制及其对IL-10和TNFR的依赖性。我们还将评估补偿pgrn缺陷小鼠的IL-10缺陷是否可以减轻它们对微生物诱导的感染性休克的易感性；以及重组PGRN是否能保护小鼠免于败血症致死亡。该应用程序的长期目标是深入了解宿主如何调节对炎症攻击（如微生物和创伤）的免疫反应，并为开发更好的全身性炎症相关疾病治疗方法奠定基础。目前主要研究PGRN在体外调控巨噬细胞IL-10合成并保护宿主全身性炎症疾病的细胞和分子机制。这些研究将有助于进一步了解PGRN在全身性炎症反应综合征中的新作用和机制，并有助于开发有效干预败血症、恢复组织稳态和重建受损免疫能力的创新策略。

DESCRIPTION (provided by applicant): Progranulin (PGRN) is a cytokine widely expressed in mammalian tissues. PGRN plays important roles in embryonic development, sexual differentiation, tumorigenesis, glucose metabolism and obesity, immunity, infection and inflammation. Altered PGRN production/function has been associated with trauma, infection, malignancy, wounding, neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis, and systemic lupus erythematosus. How PGRN regulates these biological processes is poorly understood. The major hypothesis of our proposal is that PGRN controls systemic inflammation and tissue stability in a substantial part through its ability to modulate IL-10 production. Specifically, we believe that this important regulatory pathway is structured hierarchically in the following order: CCAAT/enhancer-binding protein (C/EBP) a IL-10. To test the hypothesis we will investigate the molecular mechanisms whereby the transcriptional regulator C/EBP? targeted by PGRN stimulates IL-10 gene expression at the molecular level via TNF receptor-mediated signaling. Then, we will elucidate the mechanisms of PGRN-regulated systemic inflammatory responses and their IL-10 and TNFR dependency via C/EBPa. We will also assess if compensating the IL-10 deficit in PGRN-deficient mice can ease their susceptibility to microbially induced septic shock; and whether administration of recombinant PGRN can protect mice from sepsis-induced lethality. The long-term objective of this application is to gain insights into how the host regulates immune responses to inflammatory assaults, such as microbes and trauma, and to lay the foundation for developing better therapies for systemic inflammation-related maladies. The current project focuses on the cellular and molecular mechanisms whereby PGRN regulates the synthesis of IL-10 in macrophages in vitro and protects the host in systemic inflammatory disorders. The proposed studies will provide greater understanding of the novel role and mechanism of PGRN in the systemic inflammatory response syndrome and aid in the development of innovative strategies for effective interventions in sepsis, restoration of tissue homeostasis, and reestablishment of impaired immunological competency.