Immunosuppression by leukocyte ADAM17 during sepsis

败血症期间白细胞 ADAM17 的免疫抑制

• 批准号: 8700037
• 负责人: BRUCE K WALCHECK
• 金额: $ 22.8万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700037
• 关键词: Acute; Adhesions; Age; Attenuated; Bacterial Antibiotic Resistance; Bacterial Infections; Bioavailable; Biological Assay; Blood Circulation; Blood Vessels; Cause of Death; Cell Surface Proteins; Cells; Cleaved cell; Clinical Trials; Communities; Consultations; Data; Development; Disease; Disintegrins; Drug Targeting; Exploratory/Developmental Grant; Functional disorder; Gatekeeping; Gene Targeting; Goals; Health; Hospitals; IL8RB gene; Immune response; Immunosuppression; Immunosuppressive Agents; Impairment; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Intention; Knockout Mice; Leukocytes; Ligation; Light; Malignant Neoplasms; Membrane; Metalloproteases; Minnesota; Modeling; Molecular; Mus; Neutrophil Activation; Neutrophil Infiltration; Patients; Peptide Hydrolases; Pharmacologic Substance; Phase; Play; Population; Process; Protease Inhibitor; Puncture procedure; Regulation; Research; Research Personnel; Resources; Role; Sepsis; Septic Shock; Severity of illness; Site; Supportive care; Surface; Testing; Therapeutic; Time; Tissues; United States; Universities; chemokine; chemokine receptor; cost; density; experience; high risk; improved; in vivo; in vivo imaging; inhibitor/antagonist; innovation; intravital microscopy; meetings; migration; mortality; mouse model; neutrophil; novel; novel therapeutics; pre-clinical; public health relevance; response; secondary infection; septic; therapeutic target

SUMMARY. Sepsis - a severe systemic inflammatory response to bacterial infection - is currently the tenth most common cause of death in the United States and the primary cause of death from infection in hospitals. Despite advances in supportive care and disease-specific treatments, the incidence of sepsis and the costs associated with its treatment are rising, and are predicted to increase further as the population ages. Targeting the inflammatory phase of sepsis has failed to improve survival and there is a need for new therapeutic strategies. Increasing evidence supports a central role for immunosuppression in sepsis, which enhances the opportunity for prolonged and secondary infections. For instance, impairment of neutrophil recruitment, the first leukocyte population to respond during bacterial infection, is a critical hallmark of sepsis and is directly related to the severity of the disease. At this time, a deeper understanding of the molecular mechanisms underlying neutrophil dysfunction during sepsis is needed. Our long-term goal is to bolster the neutrophil response during sepsis, especially in light of increasing bacterial resistance to antibiotics. Our research group, which provides broad expertise in leukocyte effector activities, has determined that the membrane-associated metalloprotease ADAM17 in leukocytes is an important gatekeeper of neutrophil infiltration into sites of infection. For instance, gene-targeting ADAM17 in mouse leukocytes was found to accelerate neutrophil recruitment and bacterial clearance, and significantly improve survival during sepsis. The central hypothesis of our proposal is that over-activation of ADAM17 during sepsis promotes neutrophil dysfunction. The objective of our study is to determine the mechanism by which ADAM17 regulates neutrophil recruitment and to assess the protease as a drug target for sepsis. Our preliminary findings reveal for the first time that the chemokine receptor CXCR2 in neutrophils, which directs their migration into sites of infection, is cleaved by ADAM17 upon cell activation and that the surface expression levels of CXCR2 on circulating neutrophils are down-regulated by ADAM17 during sepsis. The specific aims of this R21 (exploratory/developmental) proposal are to establish the role of CXCR2 shedding by ADAM17 in regulating neutrophil recruitment following cecal ligation and puncture, a model of acute polymicrobial sepsis (Aim 1). In addition, we will evaluate ADAM17 as a drug target for sepsis (Aim 2). Resources unique to our study include conditional ADAM17 knockout mice and highly selective and potent ADAM17 inhibitors. The impact of our study is that it pursues a novel angle for developing therapeutic targets to improve survival by septic patients. If successful, our study will provide new information to advance our understanding of the mechanisms of action of ADAM17 during sepsis and establish its therapeutic potential.

概括。 败血症 - 对细菌感染的严重全身性炎症反应 - 目前是第十个最常见的 美国死亡原因和医院感染死亡的主要原因。尽管 支持性护理和特定疾病治疗的进展，败血症的发生率以及相关的成本 随着人口年龄的增长，它的治疗正在上升，预计将进一步增加。定位 败血症的炎症阶段未能改善生存，需要新的治疗策略。 越来越多的证据支持败血症中免疫抑制的核心作用，从而增强了机会 用于长时间和继发感染。例如，中性粒细胞招募的损害，第一个白细胞 在细菌感染期间有反应的人群是败血症的关键标志，与 疾病的严重程度。目前，对基于分子机制的更深入了解 需要在败血症期间中性粒细胞功能障碍。我们的长期目标是增强中性粒细胞反应 在败血症期间，特别是鉴于对抗生素的细菌耐药性的增加。我们的研究小组，这是 在白细胞效应子活动中提供广泛的专业知识，已确定与膜相关 金属蛋白酶ADAM17在白细胞中是中性粒细胞浸润到地点的重要看门人 感染。例如，发现小鼠白细胞中的基因靶向ADAM17可以加速中性粒细胞 招募和细菌清除率，并显着提高败血症期间的生存率。中心假设 我们的建议是，败血症期间ADAM17的过度激活会促进中性粒细胞功能障碍。这 我们研究的目的是确定ADAM17调节中性粒细胞募集和 评估蛋白酶作为败血症的药物靶标。我们的初步发现首次揭示了 中性粒细胞中的趋化因子受体CXCR2引导其迁移到感染部位，被裂解 ADAM17在细胞激活后以及循环中性粒细胞上CXCR2的表面表达水平为 败血症期间由ADAM17下调。 R21的具体目的（探索/发展） 提案是确定ADAM17脱落CXCR2在调节嗜中性粒细胞募集中的作用 Cecal连接和穿刺，一种急性多细胞败血症的模型（AIM 1）。此外，我们将评估 ADAM17是败血症的药物靶标（AIM 2）。我们研究独有的资源包括有条件的ADAM17 敲除小鼠和高度选择性和有效的ADAM17抑制剂。我们研究的影响是它追求 用于开发治疗靶标以改善化粪池患者存活的新角度。如果成功，我们的研究 将提供新的信息，以促进我们对ADAM17行动机制的理解 败血症并建立其治疗潜力。