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：
8519525
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 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8519525
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 Psychological 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.

描述（由申请人提供）：当细菌逃避宿主防御并进入血液时，随之而来的是败血症的临床综合征。尽管细菌会直接损害宿主组织，但对细菌的过度炎症反应更常见是感染过程中器官衰竭和死亡的原因。败血症每年在美国遭受超过700,000人的影响，并导致超过200,000人死亡。败血症的当前治疗方法包括早期抗生素和侵袭性静脉液体。但是，旨在使导致器官损伤的免疫反应平静下来的治疗尚未成功。为了改善这种常见和毁灭性疾病的死亡率，需要基于新的生物学发现的新治疗策略。越来越多的证据表明神经向免疫细胞发送信号，这些信号调节免疫细胞对各种刺激的反应。该研究建议的目的是研究神经在败血症期间如何调节免疫系统。具体而言，该研究建议旨在确定导致“战斗或飞行”反应的交感神经系统如何改变感染期间的生存。前研究表明，在压力期间，从交感神经释放的化合物减少了去甲肾上腺素的释放，可改善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）如何在感染过程中相互作用。具体而言，AIM 1将研究去甲肾上腺素的阿比丁素如何改变小鼠和大鼠的血液动力学。 AIM 2将识别巨噬细胞上的细胞受体，这些巨噬细胞有助于压力激素对免疫细胞信号。最后，目标3的目标是确定检测应力激素的信号传导途径如何与检测细菌的信号通路相互作用。为了研究这些目的，将进行生存研究和宿主对感染反应（细菌负荷，细胞计数，炎症细胞因子）的测量。另外，在细胞培养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，所有这些细胞培养发现的相关性将在使用骨髓移植和转基因小鼠的小鼠感染模型中测试。拟议的研究的长期目标是确定可能转化为败血症疗法的新生物学机制。这些研究还可以说明外源性去甲肾上腺素的全身给药，该肾上腺素通常用于增加重症患者的血压，改变免疫力。最后，这些研究可能阐明了慢性生理或心理压力如何改变感染的敏感性。