Project 2: Host-Pathogen Interactions in Blood Glycoprotein Modulation of Sepsis

项目 2：脓毒症血液糖蛋白调节中的宿主-病原体相互作用

• 批准号: 9072754
• 负责人: MICHAEL J MAHAN
• 金额: $ 45.23万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9072754
• 关键词: Address; Affect; Aging; Alkaline Phosphatase; Biological; Biomedical Research; Blood; Blood Coagulation Disorders; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Blood coagulation; Cessation of life; Coagulation Process; Comparative Study; Core Facility; Data; Diagnostic; Disease; Drug Metabolic Detoxication; Escherichia coli; Escherichia coli Infections; Face; Gap Junctions; Glycoproteins; Health; Hematology; Hepatocyte; Human; Immune response; Infection; Inflammation; Inflammatory Response; Isoenzymes; Knowledge; Lead; Lethal Dose 50; Life; Lipopolysaccharides; Liver; Measurement; Microbe; Modeling; Mus; Organ; Outcome; Pathogenesis; Patients; Plasma; Pneumococcal Infections; Positioning Attribute; Predisposition; Protein Dephosphorylation; Protein Glycosylation; Proteins; Regulation; Research; Research Proposals; Resistance; Role; Salmonella; Salmonella enterica; Salmonella typhimurium; Sepsis; Sepsis Syndrome; Serologic tests; Survivors; Syndrome; Testing; Therapeutic; Thrombosis; Tissues; Virulence; Virulent; disability; inorganic phosphate; microbial; mortality; novel; novel marker; pathogen; phosphatase inhibitor; programs; receptor; receptor function

SUMMARY Sepsis is one of the most common and life-threatening syndromes faced by patients and clinicians. It is often fatal due to the coagulopathy and inflammation that arises in multiple tissues from the host response, while survivors may face a lifetime of disability from the resulting vascular and organ damage. This project is focused on this major health problem while addressing the central hypothesis of this program, that protein glycosylation and glycoprotein remodeling modulate the coagulopathy and inflammation of sepsis. It has recently been determined that hepatocytes of the liver control the abundance of circulating secreted proteins that modulate thrombosis and inflammation during sepsis. This occurs by a mechanism of secreted protein aging and turnover that includes the endocytic Ashwell-Morell receptor (AMR). Unlike the previously described protective role of the AMR in sepsis caused by Gram-positive pneumococcal infection, preliminary data have recently determined that AMR function is deleterious to the host during sepsis caused by the Gram-negative bacterial pathogen Salmonella enterica Typhimurium (ST). These findings suggest that the AMR is positioned at a nexus determining host susceptibility to different microbial pathogens. These findings further indicate that the pathogenesis of sepsis may be stratified by different host responses to different pathogens, which would advance the understanding of sepsis beyond that of a singular disease mechanism. This project will investigate the mechanisms of AMR function involving Asgr1 and Asgr2 in host interactions that participate in the pathogenesis of Gram-negative bacterial sepsis to include ST and Escherichia coli (EC), with parallel studies of the underlying Systemic Inflammatory Response Syndrome (SIRS). Other preliminary data indicate a role of AMR function in host outcomes following infection by the hypervirulent strain Salmonella Choleraesuis (SC), a serovar recently discovered to be among the most virulent microbes encountered of this species. Preliminary data indicate that secreted alkaline phosphatase isozymes are regulated by the AMR and that this regulation determines the progression and outcome of Gram-negative bacterial sepsis, perhaps by dephosphorylation and detoxification of bacterial lipopolysaccharide. The roles of AP isozyme regulation in host-pathogen interactions of sepsis caused by ST, SC, and EC infection will be determined by research that includes all of the core facilities proposed. Studies proposed will further determine whether the AMR functions to modulate mechanisms of microbial hypervirulence in aims that include comparing sepsis caused by SC infection. This project will further identify the repertoire of secreted proteins regulated by the AMR in sepsis and SIRS, which may disclose novel biomarkers and proteins that are implicated in additional mechanisms that modulate the coagulopathy and inflammation of sepsis. These studies may stratify host responses to sepsis involving the AMR and different pathogens while identifying mechanisms that lead to diagnostic and therapeutic advances.

概括 脓毒症是患者和临床医生面临的最常见且危及生命的综合征之一。常常是 由于宿主反应在多个组织中出现凝血障碍和炎症而致命，而 幸存者可能因由此造成的血管和器官损伤而面临终生残疾。本项目重点 关于这个主要的健康问题，同时解决该计划的中心假设，即蛋白质糖基化 糖蛋白重塑调节脓毒症的凝血病和炎症。最近已经是 确定肝脏的肝细胞控制着调节循环分泌蛋白的丰度 败血症期间的血栓形成和炎症。这是通过分泌蛋白质老化的机制发生的 包括内吞 Ashwell-Morell 受体 (AMR) 的周转率。与前面描述的保护不同 AMR 在革兰氏阳性肺炎球菌感染引起的脓毒症中的作用，最近有初步数据 确定 AMR 功能在革兰氏阴性细菌引起的败血症期间对宿主有害 病原体 鼠伤寒沙门氏菌 (ST)。这些发现表明，AMR 的定位是 关系决定宿主对不同微生物病原体的易感性。这些发现进一步表明 脓毒症的发病机制可能根据宿主对不同病原体的不同反应进行分层，这将 促进对脓毒症的理解超越单一疾病机制。本项目将调查 涉及 Asgr1 和 Asgr2 参与宿主相互作用的 AMR 功能机制 革兰氏阴性细菌败血症的发病机制，包括 ST 和大肠杆菌 (EC)，并进行平行研究 潜在的全身炎症反应综合征（SIRS）。其他初步数据表明 AMR 在感染高毒力菌株猪霍乱沙门氏菌 (SC)（一种 最近发现血清型是该物种中毒性最强的微生物之一。初步的 数据表明，分泌型碱性磷酸酶同工酶受 AMR 调节，并且这种调节 可能通过去磷酸化决定革兰氏阴性细菌败血症的进展和结果 以及细菌脂多糖的解毒作用。 AP同工酶调节在宿主病原体中的作用 ST、SC 和 EC 感染引起的脓毒症之间的相互作用将通过包括所有这些因素的研究来确定 拟议的核心设施。拟议的研究将进一步确定 AMR 是否具有调节功能 微生物高毒力的机制，包括比较 SC 感染引起的脓毒症。这 项目将进一步确定脓毒症和 SIRS 中 AMR 调节的分泌蛋白库， 可能会公开与调节其他机制有关的新生物标志物和蛋白质 凝血障碍和脓毒症炎症。这些研究可能会分层宿主对脓毒症的反应，涉及 AMR 和不同的病原体，同时确定导致诊断和治疗进展的机制。