Analysis of ADAM10 in infection-associated MODS

ADAM10 在感染相关 MODS 中的分析

• 批准号: 9379668
• 负责人: Juliane Bubeck Wardenburg
• 金额: $ 22.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-19 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9379668
• 关键词: Active Sites; Antimicrobial Resistance; Bacteroides fragilis; Binding; Biological; Biology; Blood Coagulation Disorders; Blood Platelets; Cell physiology; Cells; Cessation of life; Characteristics; Child; Childhood; Cleaved cell; Clinical; Clinical Data; Clinical Trials; Coupled; DTR gene; Development; Disease; Disintegrins; Employee Strikes; Ephrins; Epidemiology; Epithelial; Etiology; Evaluation; Event; Failure; Family; Focal Infection; Functional disorder; Genetic Polymorphism; Goals; Homeostasis; Human; Hypoxemia; Individual; Infection; Inflammation; Injury; International; Investigation; Knockout Mice; Knowledge; Life; Light; Link; Lung; Measures; Mediating; Membrane; Metalloproteases; Modeling; Molecular; Morbidity - disease rate; Multiple Organ Failure; Myelogenous; Nature; Normal tissue morphology; Organ; Pathogenesis; Pathologic; Pathway interactions; Platelet Glycoproteins; Pneumonia; Population Study; Positioning Attribute; Prevalence; Preventive; Process; Progressive Disease; Proteins; Public Health; Refractory; Risk; Role; Safety; Sepsis; Septic Shock; Shapes; Signal Transduction; Staphylococcus alpha toxin; Staphylococcus aureus; Supportive care; Systemic disease; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxin; Ursidae Family; Vascular Endothelium; Zinc; alpha Toxin; antimicrobial; base; body system; cadherin 5; catalyst; cell type; chemokine; cytokine; endothelial dysfunction; immunoregulation; in vivo; inhibitor/antagonist; innovation; insight; member; microorganism; mortality; notch protein; novel; novel strategies; pathogen; promoter; receptor; small molecule

PROJECT SUMMARY Death related to severe infection, or sepsis, is inextricably linked to the refractory failure of one or more organ systems. While advances have been made in understanding key molecular mechanisms by which specific microorganisms cause severe infection, we still have a poor understanding of how a diverse array of human pathogens elicit the rapid progression of systemic disease defined as multiple organ dysfunction syndrome (MODS). Among children with sepsis, over 90% demonstrate multi-organ dysfunction, providing a clinical imperative to understand fundamental mechanisms by which pediatric sepsis causes MODS. With rising rates of antimicrobial resistance and the refractory nature of MODS, a deeper understanding of how localized infection converts to life-threatening systemic disease is needed. We have demonstrated the role of zinc dependent metalloproteases in the pathogenesis of lethal infection caused by S. aureus and B. fragilis – two leading etiologic agents of human sepsis. S. aureus α-toxin utilizes host ADAM10 (A Disintegrin and Metalloprotease 10) as its cellular receptor, triggering untimely, pathologic activation of the metalloprotease. The B. fragilis toxin (BFT) is a zinc dependent metalloprotease similar to ADAM10. ADAM10 and BFT both contribute to lethal infection-associated MODS. Based on these findings, we propose that infection-associated MODS is catalyzed by aberrant activation of host ADAM10. As ADAM10 is ubiquitously expressed and involved in diverse host cellular processes, this metalloprotease is well-positioned to cause the scope of injuries observed in MODS. The primary goal of this proposal is thus to examine the hypothesis that ADAM10 is required for the development of MODS in the setting of severe pneumonia and bloodstream infection caused by key human bacterial and fungal pathogens. This proposal is based on three discoveries: 1) Cell-type specific ADAM10 knockout mice permit the identification of effects of S. aureus α-toxin on individual cells in lethal infection, revealing that these depend on toxin-mediated activation of ADAM10 and pathologic cleavage of native ADAM10 substrates. 2) Infection-related organ dysfunction is a composite of ADAM10 action on discrete cells, integrated in the tissue over time. 3) A specific polymorphism in human ADAM10 predisposes toward the development of severe sepsis, irrespective of the inciting pathogen. Extending these observations toward the in vivo analysis of the broader role of ADAM10 in MODS as proposed will provide an opportunity to examine the innovative hypothesis that a host metalloprotease is critical for MODS. As specific inhibitors of ADAM10 have demonstrated safety in human clinical trials, knowledge gained from these studies may enable the evaluation of a novel class of therapeutics for infection-associated MODS.

项目摘要 与严重感染或败血症有关的死亡与一个或多个器官的难治性失效密不可分 系统。尽管在理解特定的关键分子机制方面取得了进步 微生物引起严重的感染，我们仍然对人类潜水员阵列的了解很差 病原体引起的全身性疾病的快速发展被定义为多器官功能障碍综合征 （mod）。在患有败血症的儿童中，超过90％的儿童表现出多器官功能障碍，提供了临床 必须了解小儿脓毒症会导致mod的基本机制。利率上升 mod的抗菌素耐药性和难治性，对如何局限 感染需要转化为威胁生命的全身疾病。我们已经证明了锌的作用 金黄色葡萄球菌和脆弱链球菌引起的致死感染的发病机理中的依赖金属蛋白酶 - 两个 人类败血症的领先病因学剂。金黄色葡萄球菌α-毒素利用宿主ADAM10（崩解蛋白和 金属蛋白酶10）作为其细胞受体，触发金属蛋白酶的病理激活。 脆弱芽孢杆菌毒素（BFT）是类似于ADAM10的锌依赖金属蛋白酶。 ADAM10和BFT 有助于致命感染相关的mod。根据这些发现，我们提出了与感染相关的 MODS通过异常激活ADAM10催化。因为ADAM10无处不在，并且 参与潜水员宿主的细胞过程，这种金属蛋白酶的位置很好，以引起范围 在mod中观察到的伤害。因此，该提案的主要目的是检查ADAM10的假设 在严重的肺炎和血液感染的情况下开发mod需要 由关键的人类细菌和真菌病原体。该建议基于三个发现：1）细胞类型 特定的ADAM10敲除小鼠允许鉴定金黄色葡萄球菌α-毒素对单个细胞中单个细胞的影响 致命感染，表明这些依赖于毒素介导的ADAM10和病理裂解的激活 天然ADAM10底物的。 2）与感染相关的器官功能障碍是ADAM10作用的复合材料 离散的细胞，随着时间的推移整合在组织中。 3）人ADAM10中的特定多态性易感性 不论煽动病原体，都要发育严重的败血症。扩展这些观察结果 按照拟议的Mods对ADAM10在MOD中的广泛作用进行体内分析，将为机会提供机会 检查创新的假设，即宿主金属蛋白酶对mod至关重要。作为特定的抑制剂 ADAM10在人类临床试验中表现出安全性，从这些研究中获得的知识可能会启用 对与感染相关的MOD的新型治疗的评估。