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：
8920590
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 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8920590
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（由适用提供）：败血症是医学上的一个主要问题，并危及美国近80万人的健康，杀死> 200,000。该赠款前几年所支持的工作的最新知识表明，中性电路调节细胞因子的产生，以防止潜在的伤害感染。这使得实验药物能够改变神经免疫串扰，并防止败血症致命感染。炎症反射的典型迷走神经回路通过需要通过细胞因子生产巨噬细胞表达的7 NACHR来抑制Sleen中的细胞因子产生。 sleen中的神经纤维缺乏乙酰胆碱产生所需的酶促机制，但我们最近确定了乙酰胆碱产生的T细胞群，这是炎症反射的细胞因子抑制机制所必需的。在撰写本文中，这些数据在科学领域发表，提供了证据调查结果的创新和意义。我们要求资金专注于下一个未解决的问题。在这里，我们假设产生乙酰胆碱的T细胞在严重败血症期间的细胞因子产生中起关键作用，并且在这种神经到免疫途径中靶向这些细胞将有助于为严重败血症的实验疗法开发。该假设将在以下三个特定目的中解决：具体目的1。研究乙酰胆碱产生T细胞在脓毒症存活中的作用。具体目的2。研究T细胞乙酰胆碱产生的分子机制。具体目的3。开发靶向T细胞乙酰胆碱释放的实验疗法。我们建议利用一种创新的策略选择性地分离乙酰胆碱合成T细胞，然后敲除聊天表达式以研究聊天表达以提供保护的特定要求。这项研究的成功完成将提供重要的数据，可用于调节这种神经元电路，以开发治疗方式，以预防和治疗败血症/败血性休克。

项目成果

期刊论文数量（53）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Understanding immunity requires more than immunology.

DOI：
10.1038/ni0710-561
发表时间：
2010-07
期刊：
Nature immunology
影响因子：
30.5
作者：
Tracey KJ
通讯作者：
Tracey KJ

Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation.

DOI：
10.1016/j.bbi.2014.07.010
发表时间：
2015-02
期刊：
Brain, behavior, and immunity
影响因子：
0
作者：
Rosas-Ballina M;Valdés-Ferrer SI;Dancho ME;Ochani M;Katz D;Cheng KF;Olofsson PS;Chavan SS;Al-Abed Y;Tracey KJ;Pavlov VA
通讯作者：
Pavlov VA

Acetylcholine regulation of synoviocyte cytokine expression by the alpha7 nicotinic receptor.

DOI：
10.1002/art.23987
发表时间：
2008-11
期刊：
ARTHRITIS AND RHEUMATISM
影响因子：
0
作者：
Waldburger, Jean-Marc;Boyle, David. L.;Pavlov, Valentin A.;Tracey, Kevin J.;Firestein, Gary S.
通讯作者：
Firestein, Gary S.

The vagus nerve and the inflammatory reflex--linking immunity and metabolism.