Defining gastric vagal mechanisms underlying emetic activation using novel electrophysiological and optical mapping technology

使用新型电生理学和光学映射技术定义催吐激活背后的胃迷走神经机制

• 批准号: 9054218
• 负责人: Charles Christopher Horn
• 金额: $ 29.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9054218
• 关键词: Abdomen; Absent Reflex; Axon; Biological; Boxing; Caliber; Cervical; Chemicals; Chemotherapy-Oncologic Procedure; Chronic; Cisplatin; Code; Copper Sulfate; Data; Dependence; Desire for food; Development; Devices; Disease; Electric Stimulation; Electrophysiology (science); Emetics; Etiology; Fascicle; Fiber; Future; Gastric Balloon; Gastrointestinal Diseases; Goals; Horns; Human; In Vitro; Individual; Intravenous; Joints; Jordan; Lasers; Lead; Lighting; Location; Mammals; Maps; Measures; Mechanical Stimulation; Mechanics; Medical; Molecular; Monitor; Mus; Nausea; Nausea and Vomiting; Nutritional; Optics; Organ; Pathway interactions; Patients; Pattern; Peripheral; Peripheral Nerves; Physiological; Physiology; Play; Population; Preparation; Rattus; Recording of previous events; Reflex action; Research; Role; Shrews; Signal Transduction; Spatial Distribution; Stimulus; Stomach; System; Techniques; Technology; United States National Institutes of Health; Vomiting; Work; body system; clinically relevant; diabetic gastroparesis; in vivo; innovation; irritation; knowledge base; neural circuit; new technology; novel; optical fiber; programs; public health relevance; receptive field; relating to nervous system; response; transmission process

 DESCRIPTION (provided by applicant): Nausea and vomiting occur with numerous medical treatments and diseases, including cancer chemotherapy and diabetic gastroparesis, which can lead to reduced appetite and nutritional imbalance. Activation of a gastric vagal neural circuit i believed to play a primary role in emetic signaling; however, gastric vagal emetic signaling essentially remains a "black box." The following fundamental mechanistic questions are unanswered: (1) how are emetic signals coded in the vagus by activation of specific fiber subtypes, temporal patterns, or gastric receptive fields? (2) Do different emetic stimuli produce the same vagal emetic "message"? (3) What are the mechanisms responsible for the history-dependence of the gastric emetic system? The goal of this project is to develop joint electrophysiology and infrared (IR) technology that will permit detailed functional neural circuit mapping for the control of the gastric emetic pathway as a potential therapy for nausea and emesis. Our team has the unique expertise to achieve this goal. Dr. Horn has developed a system to interrogate and analyze the activity of individual vagal units while recording the emetic reflex in the musk shrew (emetic reflexes are absent in rats and mice). Drs. Jenkins and Chiel have initiated work using an IR technology that can stimulate or inhibit sub-populations of axons with high spatial precision. Dr. Lewis has expertise in selectively activating/inhibiting vagal su-populations and in monitoring the molecular biological mechanisms associated with vagal activity. We will complete two AIMS: (1) Develop electrophysiology/IR mapping technology and apply it to characterize the topography and fiber types of gastric afferents within the vagus. To determine how fibers carrying gastric afferent signals are organized topographically within the vagus, we will develop a novel electrophysiology/IR mapping technology. We will develop a multi-optical fiber device that allows illumination of different regions circumferentially, and combine this with an electrophysiological technique that examines individual units in vagal fascicles. (2) Extend the electrophysiology/IR technology to determine and control temporal patterns of vagal activity in response to classical versus clinically relevant emetogenic stimuli. We will examine the patterning of activity in the vagus, and role of IR laser inhibition, in response to stomach-related emetic stimuli, mechanical distension, chemical irritation (using copper sulfate), and the cancer chemotherapy agent cisplatin. Our approach is innovative because we are combining cutting edge electrophysiology and IR technology to develop spatial and temporal maps of the gastric vagal organ system. This project is significant because it will elucidate precise vagal emetic mechanisms that must be modulated to control emesis; therefore, producing the critical knowledge base urgently needed to facilitate the development of new strategies to treat patients with intractable nausea and vomiting. More generally, the technology could have great utility for understanding other aspects of vagal and peripheral nerve function.

 描述（由申请人提供）：恶心和呕吐发生在许多药物治疗和疾病中，包括癌症化学疗法和糖尿病性胃癌，这会导致食欲减少和营养失衡。被认为在催吐信号中起主要作用的胃迷走神经回路的激活；但是，胃迷走神经信号基本上仍然是“黑匣子”。以下基本的机理问题未得到解决：（1）如何通过激活特定的纤维亚型，临时模式或胃接收场来在迷走神经中编码吐出信号？ （2）不同的催眠刺激会产生相同的迷走神经“消息”？ （3）造成胃吐气系统历史依赖性的机制是什么？该项目的目的是开发关节电生理学和红外线（IR）技术，该技术将允许详细的功能神经回路映射，以控制胃催吐途径，以作为恶心和发育的潜在疗法。我们的团队具有实现这一目标的独特专业知识。 Horn博士开发了一个系统来询问和分析单个迷走神经单位的活动，同时记录呕吐 肌肉sh中的反射（大鼠和小鼠中不存在Emity反射）。博士。詹金斯（Jenkins）和奇尔（Chiel）使用IR技术开始了工作，该技术可以刺激或抑制具有高空间精度的轴突的亚群。刘易斯博士在选择性激活/抑制迷走神经群和监测与迷走神经活动相关的分子生物学机制方面具有专业知识。我们将完成两个目的：（1）开发电生理/IR映射技术，并将其应用以表征迷宫内胃部传入的地形和纤维类型。为了确定携带胃传入信号的纤维如何在迷走神经中组织地形，我们将开发一种新型的电生理/IR映射技术。我们将开发一种多光光纤设备，该设备允许对不同区域进行照明，并将其与一种在迷走神经束中单独检查的电生理技术结合使用。 （2）扩展电生理/IR技术，以确定和控制对经典和临床相关的突出刺激的暂时模式。 我们将研究迷走神经的活性模式以及IR激光抑制作用，响应与压力相关的催吐刺激，机械延伸，化学刺激（使用硫酸盐）和癌症化学疗法顺铂。我们的方法具有创新性，因为我们将尖端电生理学和IR技术结合在一起，以开发胃迷走器官系统的空间和临时图。该项目很重要，因为它将阐明必须调节以控制弹性的精确迷走神经机制。因此，迫切需要产生关键的知识基础，以支持针对治疗恶心和呕吐患者的新策略的发展。更一般而言，该技术可能具有理解迷走神经和周围神经功能的其他方面的极大效用。