Macrophage Inactivation in Sepsis after Shock or Trauma

休克或创伤后脓毒症中巨噬细胞失活

基本信息

批准号：
8727574
负责人：
Kevin J Tracey
金额：
$ 37.07万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-30 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8727574
关键词：
Acetylcholine Action Potentials Acute Address Adrenergic Agents Animal Model Antibiotics Cause of Death Celiac ganglion Cells Choline O-Acetyltransferase Data Development Electric Stimulation Enzymes Experimental Drug Development Functional disorder Funding Goals Grant HMGB1 gene Health Immune Inflammation Inflammatory Interleukin-1 Investigational Therapies Knock-out Knowledge Ligation Link Liquid substance Macrophage Activation Maps Mediating Mediator of activation protein Medicine Modality Modeling Molecular Mus Nerve Nerve Fibers Neuroanatomy Neurotransmitters Nicotinic Receptors Norepinephrine Nude Mice Pathogenesis Pathway interactions Patients Persons Play Population Prevention Production Public Health Publishing Puncture procedure Reflex action Regulation Research Resuscitation Role Science Sepsis Septic Shock Severity of illness Shock Signal Transduction Source Spleen T-Lymphocyte T-Lymphocyte Subsets TNF gene Therapeutic Transgenic Mice Trauma United States Vagus nerve structure Work Writing adrenergic base clinically relevant cytokine effective therapy improved innovation insight killings macrophage mortality neural circuit neurotransmission novel prevent promoter reconstitution relating to nervous system therapeutic target vagus nerve stimulation

项目摘要

DESCRIPTION (provided by applicant): Sepsis is a major problem in medicine, and jeopardizes the health of nearly 800,000 persons in the United States annually, killing >200,000. Recent knowledge from work supported during the prior years of this grant reveals that neural circuits regulate cytokine production to prevent potentially damaging inflammation. This has enabled development of experimental drugs to modify neural-immune crosstalk, and prevent lethal inflammation in sepsis. A prototypical vagus nerve circuit, the inflammatory reflex, inhibit cytokine production in spleen through a mechanism requiring acetylcholine signaling through ¿7 nAChR expressed on cytokine- producing macrophages. Nerve fibers in spleen lack the enzymatic machinery necessary for acetylcholine production, but we have recently identified an acetylcholine-producing T cell population that is required for the cytokine inhibiting mechanism of the inflammatory reflex. At this writing, these data are in press in Science, giving evidence of the innovation and significance of the findings. We are requesting funding to focus on the next unanswered questions. Here, we hypothesize that acetylcholine-producing T cells play a pivotal role in the regulation of cytokine production during severe sepsis, and that targeting these cells in this neural to immune pathway will be useful in the development of experimental therapeutics for severe sepsis. This hypothesis will be addressed in the following three Specific Aims: Specific Aim 1. To study the role of acetylcholine producing T cells in sepsis survival. Specific Aim 2. To study the molecular mechanisms underlying T cell acetylcholine production. Specific Aim 3. To develop experimental therapeutics that target T cell acetylcholine release. We propose to utilize an innovative strategy to selectively isolate acetylcholine synthesizing T cells and then knock out ChAT expression to study the specific requirement for ChAT expression to confer protection. A successful completion of this research will provide significant data that can be used to modulate this neural circuitry to develop therapeutic modalities for the prevention and treatment of sepsis/septic shock.

描述（由申请人提供）：脓毒症是医学上的一个主要问题，每年危害美国近 800,000 人的健康，导致超过 200,000 人死亡，本拨款前几年支持的工作的最新知识表明，神经回路具有调节作用。细胞因子的产生以防止潜在的破坏性炎症，这使得开发实验药物能够改变神经免疫串扰，并预防败血症中的致命炎症。电路，即炎症反射，通过需要乙酰胆碱信号传导的机制来抑制脾脏中细胞因子的产生7 nAChR 在脾脏中产生细胞因子的巨噬细胞上表达，缺乏产生乙酰胆碱所需的酶机制，但我们最近发现了炎症反射的细胞因子抑制机制所需的产生乙酰胆碱的 T 细胞群。，这些数据发表在《科学》杂志上，证明了研究结果的创新性和意义。在此，我们发现产生乙酰胆碱的 T 细胞在严重脓毒症期间的细胞因子产生调节中发挥着关键作用，并且针对这些细胞。这种神经至免疫途径将有助于开发严重脓毒症的实验疗法。该假设将在以下三个具体目标中得到解决：具体目标 1. 研究产生乙酰胆碱的 T 细胞在脓毒症中的作用。具体目标 2. 研究 T 细胞乙酰胆碱产生的分子机制。具体目标 3. 开发针对 T 细胞乙酰胆碱释放的实验疗法。 ChAT 表达来研究 ChAT 表达提供保护的具体要求。这项研究的成功完成将提供重要的数据，可用于调节该神经回路以开发治疗方式。预防和治疗败血症/败血性休克。