Evaluating Resolution Mechanisms for Infectious Inflammation

评估感染性炎症的解决机制

• 批准号: 10352384
• 负责人: Charles Nicholas Serhan
• 金额: $ 74.58万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352384
• 关键词: Acute; Address; Anabolism; Animal Model; Blood; CD59 Antigen; Chemicals; Disease; Failure; Family; Financial Hardship; Heart; Human; Infection; Inflammation; Inflammatory Response; Intervention; Knowledge; Laboratories; Lead; Life; Lipoxins; Lung; Maps; Mediator of activation protein; Microbe; Mission; Molecular; Monitor; National Institute of General Medical Sciences; Nosocomial Infections; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Patient Care; Pharmacology; Phase; Physiology; Public Health; Recovery; Recurrence; Resolution; Sepsis; Shapes; Signal Transduction; Structure; Technology; Time; Trauma; defense response; design; experimental study; flexibility; human tissue; improved; innovation; macrophage; mortality; neutrophil; novel; pre-clinical; programs; resilience; response; septic patients

Project Summary/Abstract Sepsis is a significant public health concern with substantial financial burden in the USA. Mortality is alarmingly high in sepsis recurrence. Whether by trauma or nosocomial infection, microbes can give rise to uncontrolled infectious inflammation that impacts millions. Therefore, a deeper knowledge is needed of the endogenous resolution mechanisms as well as their potential failure(s) to resolve sepsis. The acute inflammatory response is protective; yet, when uncontrolled, inflammation is associated with many diseases, trauma, and surgical interventions that can lead to sepsis and loss of life. Resolution of inflammation was widely held to be a passive response and today is considered an exciting and essentially untapped terrain for new interventions. In self-limited inflammation, the PI first mapped and elucidated the structures, biosynthesis and functions of novel families of resolution phase mediators collectively termed specialized pro-resolving mediators (SPM). The SPM superfamily include lipoxins, resolvins, protectins and maresins where each family is proven to actively stimulate the resolution of inflammation, infections and are organ protective (i.e. lung, heart, neuroprotective) in pre-clinical animal models. In human tissues, cellular and molecular understanding of resolution programs for infectious inflammation is critically needed to harness the endogenous chemical signals that resolve innate responses to bacterial challenge. SPM target both human neutrophils and macrophages that are central in initiating the inflammatory response for defense as well as its timely resolution. In this R35 MIRA application, the PI shall focus on addressing critical gaps and challenges in the field of resolution of inflammation relevant to human infectious inflammation, sepsis and recurrence. The main overarching question and challenge to be addressed focuses on the general mission of determining whether failed resolution mechanisms in inflammation contribute to poor outcomes in sepsis or its recurrence and to identify these new components. This information is critically needed and must be obtained from accessible human tissues such as blood so that they can be swiftly implemented. Results from these will help stratify and shape the basis of new strategies for monitoring resolution mechanisms and pathways as well as their potential failure in human sepsis. Addressing these fundamental questions on the resolution of inflammation is the thrust of this MIRA application and are designed using new innovative approaches and technologies in place in the PI’s laboratory from NIGMS support. The PI has a record of innovation, and the flexibility of a MIRA will enable obtaining critical new information on mechanisms of SPM in resolution of infectious inflammation needed in the long-term, to carry out well-informed new treatment approaches for sepsis and other maladies that involve and will require taking into account resilience and the resolution response in inflammation.

项目概要/摘要 败血症是一个重大的公共卫生问题，在美国造成巨大的经济负担，死亡率惊人。 无论是外伤还是院内感染，败血症复发率都很高。 因此，需要对内源性炎症有更深入的了解。 解决机制以及解决脓毒症的潜在失败。 具有保护性；然而，如果不加以控制，炎症与许多疾病、创伤和手术有关 人们普遍认为，可能导致败血症和死亡的干预措施是解决炎症问题的关键。 被动反应，而今天被认为是一个令人兴奋且基本上尚未开发的新干预领域。 在自限性炎症中，PI首先绘制并阐明了以下物质的结构、生物合成和功能： 解决阶段介体的新家族统称为专门的促解决介体（SPM）。 SPM 超家族包括脂氧素、分解素、保护素和 maresins，其中每个家族都被证明具有 积极刺激炎症、感染的消退，并保护器官（即肺、心脏、 神经保护）在临床前动物模型中对人体组织、细胞和分子的了解。 迫切需要针对感染性炎症的解决方案来利用内源性化学物质 解决对细菌攻击的先天反应的信号针对人类中性粒细胞和 巨噬细胞在启动防御炎症反应及其及时解决方面发挥着核心作用。 在此 R35 MIRA 应用中，PI 应重点解决以下领域的关键差距和挑战： 解决与人类感染性炎症、败血症和复发相关的炎症。 要解决的首要问题和挑战侧重于确定是否 失败的解决机制会导致炎症、败血症或其复发的不良结果以及 识别这些新组件是非常需要的，并且必须从可访问的地方获取。 人体组织，例如血液，以便能够迅速实施这些结果将有助于分层和分析。 为监测解决机制和途径及其途径奠定新战略的基础 解决人类败血症的潜在失败是解决炎症的这些基本问题。 MIRA 应用程序的主旨，并采用新的创新方法和技术进行设计 在 NIGMS 的支持下在 PI 实验室中占有一席之地 PI 拥有创新记录和灵活性。 MIRA 将能够获得有关 SPM 解决感染性疾病机制的重要新信息 长期需要炎症，以对脓毒症和 其他涉及并需要考虑复原力和解决反应的疾病 炎。