Syndecan Regulation of Sepsis Host Defense

Syndecan 对脓毒症宿主防御的调节

• 批准号: 9759980
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759980
• 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; Inflammation; Inflammatory; Injury; Innate Immune Response; Integrins; Interferons; Knowledge; Lead; Leukocytes; Mediator of activation protein; Molecular; Molecular Conformation; Mus; Natural Immunity; Neutrophil Infiltration; Organ; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Production; Regulation; Resistance; Risk Factors; Sepsis; Signal Pathway; Signal Transduction; Site; Structure; Surface; Syndrome; Testing; Therapeutic; Tissues; Unspecified or Sulfate Ion Sulfates; Wild Type Mouse; adverse outcome; antimicrobial peptide; cecal ligation puncture; chemokine; combat; cost; cytokine; desensitization; efficacy testing; extracellular; gain of function; in vivo; microbial; migration; mortality; multiorgan injury; neutrophil; new therapeutic target; paracrine; pathogen; polymicrobial sepsis; pre-clinical; programs; recruit; response; septic; syndecan; tissue regeneration; tissue repair

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.

败血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发展