Metabolic and purinergic immune regulation

代谢和嘌呤能免疫调节

基本信息

批准号：
10826864
负责人：
WOLFGANG G JUNGER
金额：
$ 39.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10826864
关键词：
Bacterial Infections Biological Response Modifiers Cause of Death Cell physiology Cells Circulation Coenzyme A Coenzymes Consumption Critical Care Defect Disease Feedback Functional disorder Goals Health Homeostasis Host Defense Immune Immune System Diseases Immunosuppression Immunotherapy Impairment Infection Inflammation Intensive Care Units Intercept Intervention Invaded Knowledge Laboratories Metabolic Metabolism Mitochondria Molecular Morbidity - disease rate Multiple Organ Failure Nucleotides Organ Organ failure Outcome Patients Persons Process Purinoceptor Research Risk Reduction Sepsis Signal Pathway Signal Transduction Sirtuins T-Lymphocyte Time Trauma United States Work autocrine effective therapy fighting immune function immunoregulation improved improved outcome innovation microorganism mitochondrial dysfunction mitochondrial metabolism mortality neutrophil novel pathogen pharmacologic prevent programs response septic patients synergism therapeutic target trafficking

项目摘要

Project Summary/Abstract: Sepsis is a leading cause of death that kills more than 5 million people annually word-wide. Sepsis involves immune dysfunction that is characterized by excessive inflammation that causes multiple organ dysfunction syndrome (MODS). At the same time, immunosuppression and T cell dysfunction impair host immune defenses, resulting in the unimpeded spread of bacterial infections. Despite intense research efforts in the field, all previous attempts to improve outcome in sepsis have failed and no effective treatments are available. These disappointing results clearly demonstrate the need for a better understanding of the underlying mechanisms that cause immune dysfunction in sepsis. The focus of this laboratory has been to determine the molecular and cellular mechanisms that cause immune dysfunction in trauma, critical care, and sepsis patients. Our long-term goal is to identify novel pharmacological strategies that can prevent excessive inflammation and the immunosuppression responsible for morbidity and mortality in sepsis. We discovered novel signaling mechanisms that regulate neutrophils and T cells and that represent promising therapeutic targets to restore immune homeostasis in sepsis patients. These novel signaling mechanisms regulate cell functions by cellular ATP release and by autocrine feedback through excitatory and inhibitory purinergic receptors that act in synergy with Ca2+ signaling and mitochondrial metabolism to fine-tune the immune cell responses needed for host defense. We found that the subcellular localization and differential activation of mitochondria and purinergic receptors are essential for proper neutrophil and T cell functions. Interfering with these signaling processes impairs the ability of these cells to detect and eliminate invading pathogens. We found that these novel cell signaling pathways are impaired in sepsis patients because excessive systemic ATP that accumulates in the circulation of these patients interferes with the autocrine purinergic signaling mechanisms that regulate immune cell functions. In addition, we found that sepsis impairs the mitochondria that provide the ATP for these purinergic signaling mechanisms. In the proposed MIRA project, we plan to continue our studies in order to define the molecular and cellular mechanisms that lead to immune dysfunction in sepsis. NAD is a nucleotide that functions as a coenzyme for many metabolic processes. We will examine whether and how declining NAD levels in sepsis contribute to mitochondrial dysfunction, immune defects, and poor outcome in sepsis. We will study whether increased expression of CD38 in sepsis is responsible for increased NAD consumption and whether NAD consumption deprives sirtuins of the coenzyme they need to prevent mitochondrial damage and prevent immune cell dysfunction. In addition, we will study how purinergic signaling contributes to the activation and trafficking of mitochondria within T cells and neutrophils and how these regulatory mechanisms are impaired in sepsis. Finally, we will explore how CD38, NAD, and sirtuins can be targeted with pharmacological interventions in order to restore mitochondrial function, purinergic signaling, and immune homeostasis in sepsis patients. The proposed work is innovative and possibly paradigm shifting because it focuses on the novel concept that mitochondria are central regulators of immune cells and that mitochondrial dysfunction is the underlying problem that impairs immune function in sepsis. We propose to exploit this knowledge with innovative treatments that replenish mitochondrial health and purinergic signaling and thereby restore immune function from within the cell. This approach is superior to previous strategies aimed at intercepting stimulatory immune cell signals that failed because these strategies further disrupted immune homeostasis and the ability of the host to fight infections.

项目摘要/摘要：败血症是死亡的主要原因，每年杀死超过500万人的言语。脓毒症涉及免疫功能障碍的特征是引起多个器官功能障碍的过度炎症综合征（mods）。同时，免疫抑制和T细胞功能障碍损害宿主免疫防御性，导致细菌感染的不受阻碍。尽管在领域，以前的所有改善败血症结果的尝试都失败了，没有有效的治疗方法。这些令人失望的结果清楚地表明需要更好地理解基础引起败血症免疫功能障碍的机制。该实验室的重点是确定引起免疫的分子和细胞机制创伤，重症监护和败血症患者功能障碍。我们的长期目标是确定新颖的药理可以防止过度炎症和免疫抑制造成发病率和免疫抑制的策略败血症的死亡率。我们发现了调节嗜中性粒细胞和T细胞的新型信号传导机制，并且代表有前途的治疗靶标，可恢复败血症患者的免疫稳态。这些小说信号传导机制通过细胞ATP释放和自分泌反馈来调节细胞功能与Ca2+信号和线粒体协同作用的兴奋性和抑制性嘌呤能受体代谢以微调宿主防御所需的免疫细胞反应。我们发现亚细胞线粒体和嘌呤能受体的定位和差异激活对于适当中性粒细胞和T细胞功能。干扰这些信号过程会损害这些单元的能力检测并消除入侵的病原体。我们发现这些新颖的细胞信号通路在败血症患者，因为在这些患者的循环中积累过多的全身性ATP 干扰调节免疫细胞功能的自分泌嘌呤能信号传导机制。此外，我们发现败血症会损害为这些嘌呤能信号传导机制提供ATP的线粒体。在拟议的MIRA项目中，我们计划继续我们的研究以定义分子和细胞导致败血症免疫功能障碍的机制。 NAD是核苷酸，充当辅酶的核苷酸许多代谢过程。我们将研究败血症中NAD水平的下降以及如何促进败血症的线粒体功能障碍，免疫缺陷和不良预后。我们将研究是否增加败血症中CD38的表达负责增加NAD的消耗以及NAD消耗是否消耗剥夺Sirtuins的辅酶，以防止线粒体损伤并防止免疫细胞功能障碍。此外，我们将研究嘌呤能信号如何有助于激活和运输 T细胞和中性粒细胞内的线粒体以及败血症中这些调节机制如何受损。最后，我们将探讨CD38，NAD和SIRTUIN如何通过药理学干预措施作为目标为了恢复败血症患者的线粒体功能，嘌呤能信号传导和免疫稳态。拟议的工作具有创新性，并且可能是范式转移，因为它重点是新颖的概念线粒体是免疫细胞的中心调节剂，线粒体功能障碍是基础损害败血症免疫功能的问题。我们建议通过创新来利用这些知识补充线粒体健康和嘌呤能信号的治疗方法，从而恢复免疫功能从细胞内部。这种方法优于以前旨在拦截刺激性免疫的策略失败的细胞信号是因为这些策略进一步破坏了免疫稳态和宿主与感染作斗争。