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）：progranulin（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，葡萄糖代谢和肥胖，免疫，感染和炎症中起着重要作用。 PGRN产生/功能的改变与创伤，感染，恶性肿瘤，伤害，神经退行性疾病（如阿尔茨海默氏病和多发性硬化症以及全身性狼疮红斑症）有关。 PGRN如何调节这些生物学过程的理解很少。我们建议的主要假设是，PGRN通过调节IL-10产生的能力来控制大量部分的全身炎症和组织稳定性。具体而言，我们认为，这种重要的调节途径在层次上按以下顺序结构：CCAAT/增强子结合蛋白（C/EBP）A IL-10。为了检验假设，我们将研究转录调节剂C/EBP的分子机制？由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，我们将通过C/EBPA阐明PGRN调节的系统性炎症反应的机制及其IL-10和TNFR依赖性的机制。我们还将评估缺乏PGRN的小鼠中IL-10赤字是否可以减轻其微生物诱导的败血性休克的敏感性；以及重组PGRN的给药是否可以保护小鼠免受败血症诱导的致死性。该应用的长期目标是了解宿主如何调节对炎症性攻击（例如微生物和创伤）的免疫反应，并为为系统性炎症相关疾病提供更好的疗法奠定基础。当前的项目侧重于细胞和分子机制，在该机制中，PGRN在体外调节巨噬细胞中IL-10的合成并保护全身性炎症性疾病中的宿主。拟议的研究将对PGRN在系统性炎症反应综合征中的新作用和机制提供更多的了解，并有助于开发有效干预措施，恢复组织稳态的创新策略，并重新建立免疫学能力受损。