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Syndecan Regulation of Sepsis Host Defense

Syndecan 对脓毒症宿主防御的调节

基本信息

批准号：
10191013
负责人：
Pyong Woo Park
金额：
$ 50.14万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10191013
关键词：
Acute Disease Adhesions Affect Bacteria Binding Biological Blood Blood Coagulation Factor CXC Chemokines CXCL2 gene Cecum Cell surface Chronic Disease Clinical Clinical Trials Complex Containment Data Destinations Down-Regulation Endothelium Extracellular Matrix Failure Functional disorder Goals Growth Factor Heparan Sulfate Proteoglycan Heparitin Sulfate Host Defense Hypotension IL8RB gene Immune response Immunosuppression Incidence Infection Inflammatory Injury Innate Immune Response Integrins Interferons Knowledge Lead Leukocytes Mediator of activation protein Molecular Molecular Conformation Mus Natural Immunity Neutrophil Infiltration Pathway interactions Patients Peptide Hydrolases Phenotype Production Regulation Resistance Risk Factors Sepsis Signal Pathway Signal Transduction Site Structure Sulfate Surface Syndrome Testing Therapeutic Tissues Wild Type Mouse adverse outcome antimicrobial peptide cecal ligation puncture chemokine combat cost cytokine desensitization efficacy testing extracellular gain of function in vivo innate immune mechanisms microbial migration mortality multiorgan injury neutrophil new therapeutic target organ injury paracrine pathogen polymicrobial sepsis pre-clinical programs recruit response septic syndecan systemic inflammatory response tissue injury tissue regeneration tissue repair

项目摘要

Sepsis is a serious infectious inflammatory syndrome that develops when the initial host response fails to contain the infection. The mortality associated with sepsis remains unacceptably high and is still over 25% among approximately 750,000 patients annually in the US alone. Worldwide, the yearly incidence of sepsis and severe sepsis is estimated at an astounding 31 million and 24 million cases. Many mediators of sepsis have been identified, and many clinical trials have tested the efficacy of targeting these molecules and their mechanisms, but with one short-lived exception, none of these has resulted in an effective and specific treatment for sepsis. These data clearly indicate an unmet need for therapeutic options in sepsis and suggest that new targets, pathways and ideas need to be examined and existing paradigms need to be refined. Neutrophils are a fundamental component of the innate immune response and essential for microbial containment and eradication for sepsis survival. Downregulation of the innate immune response has been described to have adverse outcomes in preclinical and clinical sepsis. However, molecular mechanisms that suppress and dysregulate innate host responses have yet to be clearly defined, and this gap in knowledge represents one of the major barriers to therapeutic advances in the field. Our preliminary studies suggest that syndecan-1, a major cell surface heparan sulfate proteoglycan (HSPG), promotes severe infections in sepsis by inhibiting neutrophil recruitment to sites of infection and by inhibiting extracellular killing mechanisms of neutrophils in a heparan sulfate (HS)-dependent manner. Unlike other means of neutrophil suppression, syndecan-1 alters the efficacy of neutrophil migration prior to the onset of its journey to infection sites. This proposal will examine the hypothesis that syndecan-1 is a critical factor that regulates innate immune suppression in sepsis in 3 specific aims. Aim 1 will define the structural features that enable syndecan-1 HS to promote sepsis. Aim 2 will explore the biological mechanisms of how syndecan-1 suppresses innate immune responses in sepsis. Aim 3 will elucidate the septic pathways that lead to the shedding of syndecan-1 ectodomains and determine the significance of this mechanism in the progression of sepsis. Through these studies, the culminating goal of this proposal is to uncover previously unknown fundamental functions of syndecan-1 in sepsis and to increase our understanding of molecular and cellular pathways that are central to innate immune suppression in sepsis.

脓毒症是一种严重的感染性炎症综合征，当最初的宿主反应未能控制感染。与脓毒症相关的死亡率仍然高得令人无法接受，仍然超过25%。仅在美国每年就有大约75万名患者。在世界范围内，脓毒症的年发病率严重的脓毒症估计有3100万和2400万例，令人震惊。脓毒症的多种介质已经确定，许多临床试验已经测试了靶向这些分子和它们的有效性机制，但除了一个短暂的异常，所有这些都没有导致有效和具体的脓毒症的治疗。这些数据清楚地表明，脓毒症的治疗方案尚未得到满足，并提示需要审查新的目标、途径和想法，需要改进现有的模式。中性粒细胞是先天免疫反应的基本组成部分，对微生物来说也是必不可少的。遏制和根除败血症的生存。先天免疫反应的下调被描述为在临床前和临床败血症中有不良后果。然而，分子机制抑制和失调先天寄主反应还没有明确的定义，而这种认识上的差距是该领域治疗进展的主要障碍之一。我们的初步研究表明 Syndecan-1是一种主要的细胞表面硫酸肝素蛋白多糖(HSPG)，可促进脓毒症的严重感染通过抑制中性粒细胞募集到感染部位和通过抑制细胞外杀伤机制中性粒细胞以硫酸乙酰肝素(HS)依赖的方式。与其他抑制中性粒细胞的方法不同， Syndecan-1在中性粒细胞迁移到感染部位之前改变其疗效。这提案将检验Syndecan-1是调节先天免疫的关键因子这一假设。抑制脓毒症的3个特定目标。目标1将定义使-1\f25 Syndecan HS-1能够促进败血症。目的2探讨Syndecan-1抑制先天免疫的生物学机制脓毒症的反应。目标3将阐明导致syndecan-1脱落的败血症途径。并确定这一机制在脓毒症进展中的意义。通过这些研究，这项提议的最终目标是揭示以前未知的基本功能 Syndecan-1在脓毒症中的作用，并增加我们对关键的分子和细胞通路的了解脓毒症的先天免疫抑制。