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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（由申请人提供）：颗粒蛋白前体（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。改变的PGRN产生/功能与创伤、感染、恶性肿瘤、创伤、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相关。PGRN如何调节这些生物过程知之甚少。我们提出的主要假设是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。具体地说，我们认为，这一重要的调节途径是分层结构，在以下顺序：CCAAT/增强子结合蛋白（C/EBP）的IL-10。为了验证这一假设，我们将研究转录调节因子C/EBP？PGRN靶向的IL-10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调节全身炎症反应的机制及其通过C/EBPa的IL-10和TNFR依赖性。我们还将评估是否补偿PGRN缺陷小鼠中的IL-10缺陷可以减轻其对微生物诱导的脓毒性休克的易感性;以及重组PGRN的施用是否可以保护小鼠免受脓毒症诱导的致死性。该应用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的治疗方法奠定基础。目前的项目集中在细胞和分子机制，从而PGRN调节白细胞介素-10在体外巨噬细胞的合成，并保护主机在全身性炎症性疾病。拟议的研究将提供对PGRN在全身炎症反应综合征中的新作用和机制的更好理解，并有助于开发有效干预脓毒症、恢复组织稳态和重建受损免疫能力的创新策略。