Orexinergic Modulation of Experimental Sepsis

实验性脓毒症的食欲调节

基本信息

批准号：
9383915
负责人：
CLIFFORD Scott DEUTSCHMAN
金额：
$ 31.35万
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：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9383915
关键词：
Acute Address Adrenergic Agents Agonist American Arousal Attenuated Autonomic nervous system Brain Cardiac Catheters Cells Cessation of life Characteristics Choline O-Acetyltransferase Clinical Complex Data Disabled Persons Disease FOS gene Functional disorder HMGB1 gene Harvest Hepatic Hypothalamic structure Immune Immune response Impairment Infection Inflammation Inflammatory Inflammatory Response Infusion procedures Injection of therapeutic agent Interleukin-6 Life Ligation Locomotion Lung Mediating Metabolism Mus Muscarinic Acetylcholine Receptor Muscarinic M1 Receptor Muscarinics Neurons Neurotransmitters Nicotine Nicotinic Receptors Organ Organism Pathology Pathway interactions Peripheral Pharmaceutical Preparations Pituitary Hormones Placebos Play Process Puncture procedure Recovery Reflex action Renal function Research Role Sepsis Serum Signal Transduction Splenocyte Stress Survivors System TNF gene Temperature Testing Therapeutic Time Vagus nerve structure attenuation basal forebrain brain pathway cholinergic cohort hypocretin immune function improved intraperitoneal killings mind control mortality novel operation portion control receptor-mediated signaling respiratory response xanomeline

项目摘要

Project Summary Complex organisms protect themselves against threats via inflammation, which is in part controlled by brain pathways involving the neurotransmitter orexin. In sepsis, inflammation becomes dysregulated and organ dysfunction develops. We have shown that orexinergic activity is attenuated in experimental sepsis (cecal ligation and puncture (CLP) in mice). The main objectives of this project are to identify how sepsis-induced attenuation of orexinergic activity effects organ function, alters the host inflammatory response and contributes to mortality, and to determine if correcting decreased orexinergic activity reverses these changes. We will address these objectives via three Specific Aims. Specific Aim 1. Determine the effects of CLP-induced loss of orexinergic activity on organ function and pathology and on survival. Examine the contribution of the autonomic nervous system to these changes. Approach: We will reverse the CLP-induced loss of orexinergic activity with ICV orexin injection and examine how this alters cardiac, pulmonary, hepatic, renal and immune function, and survival. We will use peripheral β-adrenergic and muscarinic blockade to identify the contribution of the autonomic nervous system. Further, we will determine if an ICV orexin infusion delivered at several different time points improves 14-day survival. Specific Aim 2. Determine the effects of the CLP-induced loss of orexinergic activity on brain cholinergic activity and on the inflammatory reflex. Approach: We will reverse the CLP-induced loss of orexinergic activity with an ICV injection of orexin and determine how this effects basal forebrain muscarinic and inflammatory reflex activity. To accomplish this we will examine the effects of an ICV orexin injection on 1) co-localization of choline-acetyltransferase (ChAT) and c-fos immunostaining, indicative of cholinergic activity, in appropriate brain sections, 2) serum levels of TNFα, IL-6 and HMGB1 and 3) TNFα, IL-6 and HMGB1 levels in the medium of harvested, stimulated splenocytes. . Specific Aim 3. Determine the effects of CLP-induced loss of brain cholinergic activity on orexinergic activity and, as a result, on alterations in HR, RR, T and pituitary hormone secretion. Approach: We will reverse the CLP-induced loss of brain cholinergic activity with xanomeline, a central M1 agonist, or ICV nicotine, and determine if orexinergic activity and HR, RR, T and pituitary hormone secretion are restored. We will then examine the effects of the orexin antagonist almorexant Demonstrating that CLP-induced changes in the orexinergic system modulate organ dysfunction, inflammatory responses and survival could re-direct the investigative and therapeutic paradigm to focus on the brain as a primary driver of sepsis, overcoming a critical barrier to progress. Demonstrating that we can alter these effects by enhancing brain cholinergic activity could provide a new, clinically viable therapeutic avenue for use in this deadly, highly prevalent disorder.

项目摘要复杂的生物可以通过注射保护自己免受威胁，部分由大脑控制涉及神经递质OREXIN的途径。在败血症中，感染失调并组织功能障碍的发展。我们已经表明，在实验性败血症（盲肠）小鼠的结扎和穿刺（CLP））。该项目的主要目标是确定败血症诱导的衰减Orecinagin活性影响器官功能，改变宿主炎症反应和有助于死亡率，并确定校正降低的Orecinagin活性会逆转这些变化。我们将通过三个特定目标解决这些目标。具体目的1。确定CLP诱导的Orecinagrig活性丧失对器官功能的影响病理学和生存。检查自主神经系统对这些变化的贡献。方法：我们将通过ICV Orexin注入和检查逆转CLP引起的OREXIN能活性的丧失这如何改变心脏，肺，肝，肾脏和免疫学功能以及生存。我们将使用外围 β-肾上腺素和毒蕈碱阻塞，以确定自主神经系统的贡献。更远，我们将确定在几个不同时间点提供的ICV Orexin输注是否可以提高14天的生存率。具体目的2。确定CLP诱导的甲氧氨酸活性丧失对脑胆碱能的影响活动和炎症反射。方法：我们将通过ICV注射Orexin和确定这如何影响基本的前脑毒蕈碱和炎症反射活性。为了实现这一目标将检查ICV Orexin注入对1）胆碱 - 乙酰转移酶（CHAT）和在适当的大脑切片中，C-FOS免疫染色，指示胆碱能活性，2）TNFα的血清水平， IL-6和HMGB1和3）TNFα，IL-6和HMGB1水平在收获的，刺激的脾细胞中。具体目的3。确定CLP诱导的脑胆碱能活性丧失对甲状腺素能的影响结果，因此，关于人力资源，RR，T和Perutaht Horsene分泌的改变。方法：我们将用Xanomeline（中央M1）逆转CLP诱导的脑胆碱能活性的丧失激动剂或ICV尼古丁，并确定Orexinagric活性和HR，RR，T和Peratary Horsene分泌已恢复。然后，我们将检查Orexin拮抗剂酒精的效果证明CLP诱导的Orecinerangic系统的变化调节器官功能障碍，炎症反应和生存可以重新指导调查和治疗范式，以专注于大脑败血症的主要驱动力，克服了进步的关键障碍。证明我们可以改变这些通过增强大脑胆碱能活性的效果可以提供新的，临床上可行的治疗途径在这种致命的，高度普遍的疾病中。