Regulation of Innate Immunity by the Sympathetic Nervous System Druing Sepsis

脓毒症期间交感神经系统对先天免疫的调节

基本信息

批准号：
8383013
负责人：
Eric J. Seeley
金额：
$ 13.15万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8383013
关键词：
Ablation Adrenal Medulla Adrenergic Receptor Anti-Inflammatory Agents Anti-inflammatory Antibiotics Attenuated Autonomic nervous system Bacteria Bacterial Infections Binding Biology Blood Blood Pressure Bone Marrow Bone Marrow Transplantation CCL2 gene Cardiomyopathies Catecholamines Cell Count Cell Culture Techniques Cells Cessation of life Chimera organism Chronic Clinical Critical Illness Cytokine Inducible SH2-Containing Protein Goals Hormones Hospital Costs Host Defense IV Fluid Immune Immune response Immune system Immunity Immunologics Immunosuppression Immunosuppressive Agents Immunotherapy In Vitro Infection Inflammatory Inflammatory Response Injury Innovative Therapy Interleukin-6 Klebsiella pneumonia bacterium Knowledge Lead Light Measurable Measures Modeling Molecular Mus Natural Immunity Nerve Nerve Endings Norepinephrine Organ Organ failure Pathway interactions Patients Peritoneal Peritoneal Macrophages Peritonitis Physiological Predisposition Property Proteins Psychologic Stress Public Health Rattus Receptor Signaling Regulation Research Research Proposals Rodent Model Role Sepsis Sepsis Syndrome Signal Pathway Signal Transduction Signaling Molecule Stimulus Stream Stress Sympathectomy Sympathetic Nervous System TLR4 gene Testing Therapeutic Tissues Transgenic Mice Translating United States base cholinergic cytokine fighting hemodynamics immunoregulation improved in vitro testing in vivo macrophage monocyte mortality mouse model neutrophil novel novel therapeutics receptor research study response septic

项目摘要

DESCRIPTION (provided by applicant): When bacteria evade host defenses and enter the blood stream, the clinical syndrome of sepsis ensues. Although bacteria can directly damage host tissues, an over exuberant inflammatory response to bacteria is more commonly the cause of organ failure and death during infection. Sepsis afflicts over 700,000 people yearly in the United States and leads to more than 200,000 deaths. Current treatments for sepsis include early antibiotics and aggressive intravenous fluids. However, treatments aimed at calming the immune response that leads to organ damage have not been successful. New therapeutic strategies based on novel biologic discoveries are needed in order to improve mortality from this common and devastating illness. Mounting evidence indicates that nerves send signals to immune cells and that these signals regulate how immune cells respond to various stimuli. The goal of this research proposal is to investigate how nerves regulate the immune system during sepsis. Specifically, this research proposal aims to identify how the sympathetic nervous system, which leads to the "fight or flight" response, alters survival during infection. Preliminar studies indicate that decreasing the release of norepinephrine, a compound released from sympathetic nerves during stress, improves survival in mouse models of infection. The goal of the 3 research aims is to systematically investigate how norepinephrine and innate immune cells, like macrophages, interact during infection. Specifically, aim 1 will investigate how ablatin of norepinephrine alters hemodynamics in mice and rats. Aim 2 will identify the cellular receptors on macrophages that help stress hormones signal to immune cells. Lastly, the goal of aim 3 is to determine how the signaling pathways that detect stress hormones interact with the signaling pathways that detect bacteria. Survival studies and measures of host response to infection (bacterial loads, cell counts, inflammatory cytokines), will be performed in order to investigate these aims. In addition, macrophages grown in cell culture will be used to study the receptors and molecules through which norepinephrine influences macrophages function. Finally, the relevance of all of these cell culture findings will be tested in mouse models of infection using bone marrow transplants and transgenic mice. The long-term goal of the proposed research is to identify new biologic mechanisms that might translate into novel therapies for sepsis. These studies may also illustrate how the systemic administration of exogenous norepinephrine, which is commonly used to increase blood pressure in critically ill patients, alters immunity. Lastly, these studies may shed light on how chronic physiologic or psychologic stress alter susceptibility to infection. PUBLIC HEALTH RELEVANCE: This project will investigate molecular interactions between stress induced signaling molecules, like norepinephrine, and the immune system in the context of severe infection. If successful, the proposed studies would benefit public health by potentially leading to new treatments for infections.

描述（由申请人提供）：当细菌逃避宿主防御并进入血流时，就会出现败血症的临床综合征。尽管细菌可以直接损害宿主组织，但对细菌过度旺盛的炎症反应更常见是感染期间器官衰竭和死亡的原因。在美国，脓毒症每年影响超过 70 万人，并导致超过 20 万人死亡。目前脓毒症的治疗方法包括早期抗生素和侵袭性静脉输液。然而，旨在平息导致器官损伤的免疫反应的治疗尚未成功。为了降低这种常见的毁灭性疾病的死亡率，需要基于新的生物学发现的新的治疗策略。越来越多的证据表明，神经向免疫细胞发送信号，并且这些信号调节免疫细胞对各种刺激的反应。这项研究计划的目标是研究脓毒症期间神经如何调节免疫系统。具体来说，这项研究计划旨在确定导致“战斗或逃跑”反应的交感神经系统如何改变感染期间的生存。初步研究表明，减少去甲肾上腺素（一种交感神经在应激过程中释放的化合物）的释放可以提高小鼠感染模型的存活率。这 3 项研究的目的是系统地研究去甲肾上腺素和先天免疫细胞（如巨噬细胞）在感染过程中如何相互作用。具体来说，目标 1 将研究去甲肾上腺素消融如何改变小鼠和大鼠的血流动力学。目标 2 将识别巨噬细胞上的细胞受体，帮助应激激素向免疫细胞发出信号。最后，目标 3 的目标是确定检测应激激素的信号通路如何与检测细菌的信号通路相互作用。为了研究这些目标，将进行生存研究和宿主对感染反应的测量（细菌负荷、细胞计数、炎症细胞因子）。此外，在细胞培养物中生长的巨噬细胞将用于研究去甲肾上腺素影响巨噬细胞功能的受体和分子。最后，所有这些细胞培养结果的相关性将在使用骨髓移植和转基因小鼠的感染模型中进行测试。拟议研究的长期目标是确定可能转化为脓毒症新疗法的新生物学机制。这些研究还可能说明，外源性去甲肾上腺素（通常用于增加危重患者的血压）的全身给药如何改变免疫力。最后，这些研究可能揭示慢性生理或心理压力如何改变感染的易感性。公共健康相关性：该项目将研究严重感染情况下应激诱导的信号分子（如去甲肾上腺素）与免疫系统之间的分子相互作用。如果成功，拟议的研究将有利于公众健康导致感染的新治疗方法。