Training Innate Immunity: A new approach to the treatment of Sepsis

训练先天免疫：治疗脓毒症的新方法

• 批准号: 10461115
• 负责人: EDWARD R SHERWOOD
• 金额: $ 52.84万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461115
• 关键词: Acetyl Coenzyme A; Acute; Acute Respiratory Distress Syndrome; Address; Adult; Age; Age-Years; Aging; Automobile Driving; Cause of Death; Citrates; Citric Acid Cycle; Complex; Cost of Illness; Critical Illness; Data; Disease; Elderly; Event; Expenditure; FDA approved; Failure; Functional disorder; Gene Expression; Generations; Grant; Hospitals; Human; Immune; Immune System Diseases; Immune system; Immunity; Immunologic Memory; Immunosuppression; Incidence; Individual; Infection; Inflammatory Response; Innate Immune System; Institution; Intensive Care Units; Leukocytes; Maintenance; Metabolic; Mitochondria; Modeling; Molecular; Multiple Organ Failure; Natural Immunity; Organ; Outcome; Patients; Phagocytosis; Pharmaceutical Preparations; Phenotype; Production; Reporting; Research; Resistance to infection; Respiratory Burst; Respiratory distress; Role; Science; Secondary to; Sepsis; Sepsis Syndrome; Septic Shock; Severities; Shock; Signal Transduction; Systemic Inflammatory Response Syndrome; Time; Training; Training Support; United States; United States National Institutes of Health; aged; antimicrobial; beta-Glucans; clinically relevant; cognitive disability; comorbidity; cytokine; effective therapy; epigenome; epigenomics; experience; experimental study; human disease; human old age (65+); immune function; improved; in vivo; in vivo Model; innate immune mechanisms; macrophage; metabolic phenotype; monocyte; mortality; novel; novel strategies; pathogen; physically handicapped; prevent; recurrent infection; response; secondary infection; septic; septic patients; systemic inflammatory response; transcriptomics

This revised competitive renewal application is submitted under the NIH multiple PI initiative (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-11-118.html). Drs. Ed Sherwood and David Williams will serve as the PIs. The multiple PI strategy is advantageous because it enables a “team science” approach that will draw equally on the expertise and experience of both of the PIs, their research groups and their respective institutions. The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory distress syndrome, systemic inflammatory response syndrome, sepsis syndrome, septic shock and/or multiple organ dysfunction syndrome. In the United States ~951,000 patients/year develop sepsis with approximately half of these patients in the ICU and an overall mortality rate is 28.6%. Those patients that survive the initial septic event may ultimately succumb to widespread organ dysfunction that can be either acute, due to hyper-inflammatory responses, or more prolonged due to immune dysfunction. It is well accepted that sepsis causes suppression of the immune system and that sepsis-induced immunoparalysis predisposes the critically ill patient to secondary infections. Attempts at developing effective therapies to prevent or treat sepsis and its associated immunosuppression have proven to be exceedingly difficult. In fact, no drugs are currently approved by the FDA for the management of sepsis. Recent data have provided compelling evidence that the innate immune system can be “trained” to respond more rapidly and effectively to pathogens. In this revised application, we propose the novel concept that it may be possible to “train” the compromised immune system, such that an effective response can be mounted to existing and/or subsequent infections. We hypothesize that “innate immune training will reprogram the metabolic, transcriptomic, epigenomic and functional phenotype of monocytes and macrophages from patients with sepsis and confer augmented resistance to infection”. To critically evaluate this hypothesis, we propose the following specific aims. Aim 1. Define the functional role of β-glucan-induced metabolic reprogramming for inducing and sustaining trained immunity in human monocytes and macrophages. In this aim, we will explore the cellular and molecular mechanisms that are essential for induction of the trained phenotype. Specifically, we will investigate the metabolic phenotype of trained human monocyte/macrophages and determine the functional importance of metabolic reprogramming for inducing and sustaining the trained phenotype in leukocytes. Aim 2. Elucidate the mechanisms of innate immune training in human adults as a function of age. In this aim, we will examine the impact of immune training on leukocytes from aging humans. In ex vivo experiments, we will examine cytokine secretion, metabolic reprogramming, gene expression, the epigenome, mitochondrial function and the anti-microbial functions of human monocytes and macrophages in response to immune training. Aim 3. Examine the effect of immune training in leukocytes isolated from sepsis patients. In this aim, we will employ monocytes or monocyte derived macrophages from sepsis patients. We will examine the effect of immune training on metabolic reprogramming, gene expression, the epigenome, mitochondrial activity and functionality of human monocytes and macrophages from septic patients. Successful completion of this research will provide a wealth of new and novel information on the mechanisms driving trained immunity in the presence and absence of sepsis. Of greater significance, this research will investigate innate immune training as a strategy for preventing and/or ameliorating sepsis and septic sequelae in the critically ill patient.

这份修订后的竞争续签申请是根据NIH多重PI计划提交的 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-11-118.html).艾德·舍伍德博士和大卫·威廉姆斯博士 将担任私人侦察。多PI策略是有利的，因为它实现了“团队科学”方法 这将同样利用两个私人投资机构、他们的研究小组和他们的 各自的机构。危重病人经常出现复杂的疾病谱，可能 包括急性呼吸窘迫综合征、全身性炎症反应综合征、败血症综合征、 感染性休克和/或多器官功能障碍综合征。在美国，每年约有951,000名患者发展 脓毒症患者中约有一半在ICU，总死亡率为28.6%。那些 在最初的败血症事件中幸存下来的患者最终可能会死于广泛的器官功能障碍，这种功能障碍可能 要么是急性的，由于过度炎症反应，要么是由于免疫功能障碍而延长。这很好 公认败血症会导致免疫系统抑制，而败血症会导致免疫麻痹 使危重病人容易继发感染。尝试开发有效的治疗方法来 预防或治疗败血症及其相关的免疫抑制已被证明是极其困难的。事实上, 目前FDA还没有批准用于治疗脓毒症的药物。最近的数据提供了 令人信服的证据表明，可以对先天免疫系统进行“训练”，以更快、更有效地应对 病原体。在这个修订后的应用程序中，我们提出了一个新的概念，即有可能“训练” 免疫系统受损，因此可以对现有和/或后续的免疫系统进行有效的响应 感染。我们假设“先天免疫训练将重新编程新陈代谢，转录， 脓毒症患者单核细胞和巨噬细胞的表观基因组和功能表型 增强了对感染的抵抗力。为了批判性地评估这一假设，我们提出了以下建议 明确的目标。目的1.明确β-葡聚糖诱导的代谢重编程在 诱导和维持人单核细胞和巨噬细胞的训练性免疫。为了实现这一目标，我们将 探索诱导训练表型所必需的细胞和分子机制。 具体地说，我们将研究经过训练的人单核/巨噬细胞的代谢表型和 确定代谢重新编程对诱导和维持训练者的功能重要性 白细胞的表型。目的2.阐明成人AS先天免疫训练的机制 这是年龄的作用。在这个目标中，我们将检查免疫训练对老化的白细胞的影响。 人类。在体外实验中，我们将检测细胞因子的分泌、代谢重编程、基因 人单核细胞的表达、表观基因组、线粒体功能和抗微生物功能 巨噬细胞对免疫训练的反应。目的3.检测免疫训练对白细胞的影响 从败血症患者中分离出来的。在这个目标中，我们将使用单核细胞或单核细胞来源的巨噬细胞 败血症患者。我们将研究免疫训练对新陈代谢重新编程、基因表达、 脓毒症患者单核巨噬细胞的表观基因组、线粒体活性和功能 病人。这项研究的成功完成将提供丰富的关于 在存在和不存在败血症的情况下，驱动训练性免疫的机制。更重要的是，这 研究将研究先天免疫训练作为预防和/或改善脓毒症和 危重病人的败血症后遗症。