Syndecan Regulation of Sepsis Host Defense

脓毒症是一种严重的感染性炎症综合征，当最初的宿主反应失败时， 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，败血症的年发病率 严重的败血症估计有惊人的3100万和2400万病例。脓毒症的许多介质 已经确定，许多临床试验已经测试了靶向这些分子及其 机制，但除了一个短暂的例外，这些都没有导致有效和具体的 治疗败血症。这些数据清楚地表明脓毒症治疗选择的需求未得到满足，并建议 需要审查新的目标、途径和想法，需要改进现有的范例。 中性粒细胞是先天性免疫应答的基本组成部分，并且对于微生物免疫应答是必需的。 控制和根除脓毒症的生存。先天免疫反应的下调一直是 在临床前和临床脓毒症中具有不良结局。然而，分子机制， 抑制和失调先天宿主反应尚未得到明确定义， 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乙酰肝素蛋白聚糖（HSPG），促进脓毒症中的严重感染 通过抑制中性粒细胞向感染部位的募集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）依赖性方式。与其他抑制中性粒细胞的方法不同， 多配体蛋白聚糖-1在中性粒细胞迁移到感染部位之前改变其迁移的功效。这 一项提案将检验syndecan-1是调节先天免疫的关键因子这一假设 在3个特定目的中抑制脓毒症。目的1将定义使syndecan-1 HS能够 促进败血症。目的2探讨syndecan-1抑制天然免疫的生物学机制 脓毒症的反应。目的3将阐明导致syndecan-1脱落的脓毒症途径 细胞外结构域，并确定该机制在脓毒症进展中的意义。通过这些 这项研究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，并增加我们对脓毒症的核心分子和细胞途径的理解。 脓毒症的先天免疫抑制

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.