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

颗粒体蛋白前体介导的 IL-10 控制化脓性炎症的机制

基本信息

批准号：
8894237
负责人：
XIAOJING MA
金额：
$ 42.38万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8894237
关键词：
Affect Alzheimer&apos s Disease Anti-Inflammatory Agents Anti-inflammatory Biological Process Bone Marrow CCAAT-Enhancer-Binding Proteins CCL2 gene Cells Cessation of life Clinical Dependency Development Disease Embryonic Development Endotoxic Shock Endotoxins Foundations Frontotemporal Dementia Gene Expression Genes Genetic Transcription Glycoproteins Goals Health Hematopoiesis Histone Acetylation Homeostasis Human Hypersensitivity IL10 gene Immune Immune Tolerance Immune response Immunity In Vitro Infection Inflammation Inflammatory Inflammatory Response Interleukin-10 Interleukin-12 Interleukin-6 Intervention Knock-out Knockout Mice Lead Ligation Link Malignant Neoplasms Mediating Microbe Modeling Molecular Multiple Sclerosis Mus Mutation Natural Immunity Neurodegenerative Disorders Obesity PGRN gene Play Positioning Attribute Predisposition Production Progranulin Puncture procedure Receptor Signaling Recombinants Regulation Regulatory Pathway Respiratory Burst Role Sepsis Sepsis Syndrome Septic Shock Site Structure Structure-Activity Relationship Supplementation Systemic Lupus Erythematosus Systemic Therapy Testing Tissues Trauma Tumor Necrosis Factor Receptor Wound Healing assault chromatin remodeling cytokine effective intervention glucose metabolism histone modification in vivo innovation insight macrophage microbial monocyte neurotrophic factor neutrophil novel receptor-mediated signaling response restoration septic tumorigenesis

项目摘要

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.

描述（申请人提供）：颗粒体蛋白前体（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着重要作用。 PGRN 产生/功能的改变与创伤、感染、恶性肿瘤、受伤、神经退行性疾病（如阿尔茨海默病和多发性硬化症）以及系统性红斑狼疮有关。人们对 PGRN 如何调节这些生物过程知之甚少。我们提议的主要假设是 PGRN 通过其调节 IL-10 产生的能力在很大程度上控制全身炎症和组织稳定性。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）a IL-10。为了检验这一假设，我们将研究转录调节因子 C/EBP？ PGRN 靶向通过 TNF 受体介导的信号传导在分子水平上刺激 IL-10 基因表达。然后，我们将阐明PGRN调节的全身炎症反应的机制及其通过C/EBPα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引起的感染性休克的易感性；以及重组 PGRN 的施用是否可以保护小鼠免受脓毒症引起的死亡。该应用的长期目标是深入了解宿主如何调节对炎症攻击（例如微生物和创伤）的免疫反应，并为开发更好的治疗系统性炎症相关疾病的疗法奠定基础。目前的项目重点研究 PGRN 在体外调节巨噬细胞中 IL-10 的合成并在全身炎症性疾病中保护宿主的细胞和分子机制。拟议的研究将更好地了解 PGRN 在全身炎症反应综合征中的新作用和机制，并有助于制定有效干预脓毒症、恢复组织稳态和重建受损免疫能力的创新策略。