Optogenetic control of vagal afferent signaling in chemotherapy-induced nausea and emesis

化疗引起的恶心和呕吐中迷走神经传入信号的光遗传学控制

• 批准号: 9172374
• 负责人: Charles Christopher Horn
• 金额: $ 7.71万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-07 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172374
• 关键词: Adverse drug event; Adverse effects; Affect; Afferent Neurons; Afferent Pathways; Animal Model; Anorexia; Antiemetics; Calcitonin Gene-Related Peptide; Cancer Patient; Canis familiaris; Cations; Cervical; Chemotherapy-Oncologic Procedure; Chloride Ion; Chlorides; Cisplatin; Clinical Management; Cyclophosphamide; Cytotoxic Chemotherapy; Data; Dependovirus; Diabetes Mellitus; Disease; Dose; Electrocardiogram; Electrophysiology (science); Emetics; Emotional; Esophageal; Exposure to; Felis catus; Ferrets; Fiber; Gastrointestinal tract structure; Genetic; Goals; Halorhodopsins; Horns; Immunohistochemistry; Inflammation; Injection of therapeutic agent; Intestines; Isolectin; Knowledge; Label; Lead; Light; Mammals; Measures; Methods; Mus; Nausea; Nausea and Vomiting; Neurons; Nociception; Nodose Ganglion; Obesity; Operative Surgical Procedures; Opsin; Optics; Patients; Peripheral; Play; Population; Preparation; Pump; Rattus; Recombinant adeno-associated virus (rAAV); Reflex action; Reporter; Rhodopsin; Rodent; Role; Sensory; Shrews; Signal Transduction; Source; Specificity; Spinal nerve structure; Stimulus; Stomach; Substance P; TRPV1 gene; Techniques; Testing; Treatment outcome; Viral Vector; Viral load measurement; Virus; Virus Diseases; Vomiting; Work; cancer therapy; cell type; chemotherapy; economic impact; effective therapy; experience; ganglion cell; gastrointestinal; improved; in vivo; innovation; member; minimally invasive; optogenetics; receptive field; receptor; research study; response; theories; thoracic pressure; tool; transmission process

Cytotoxic chemotherapy-induced side effects, including nausea and vomiting, impose a severe physical and emotional burden on cancer patients, which can limit the use of dose-dense curative cancer therapy. Although the exact mechanisms for these adverse effects remain obscure, current theories suggest that vagal sensory signals from the gastrointestinal (GI) tract play a critical role. Until now, it has been impossible to test the function of defined vagal afferent population signaling in these responses to chemotherapy because peripheral neurons could not be selectively, and reversibly, silenced or activated; the optogenetic approach potentially removes this barrier. Here, we propose to use a small animal model for emesis testing (musk shrew) as a platform to assess modulation of GI vagal signaling. Unlike rodents, the musk shrew (a mouse-sized mammal) has a vomiting reflex and is an efficient alternative to ferrets, cats, and dogs for the study of chemotherapy-induced emesis. Our central hypothesis states that vagal afferent neurons can be optogenetically controlled to produce emesis or inhibit chemotherapy-induced emesis. We plan to test this hypothesis by pursuing two specific aims: (1) test the specificity of transport of viral vectors containing light-sensitive opsins, halorhodopsin (for inhibition) and channelrhodopsin-2 (for excitation) in GI vagal afferent populations; and, (2) determine the effects of optical modulation of vagal signaling on emesis. Adeno- associated viruses (AAVs) will be injected into specific stomach regions to infect vagal sub- populations. AAVs will also contain fluorescent reporters to permit the histological examination of sub- sets of nodose ganglia neurons. Specific wavelengths of light applied to AAV loaded vagal fibers will be used to stimulate and inhibit emesis (produced by chemotherapy) in our established in vivo electrophysiology preparation. These experiments will confirm the use of optogenetic methods to modulate vagal sensory transmission. The results of this project with be valuable in the control and testing of emetic mechanisms; similarly, optogenetic methods may be applied to assessing the role of vagal signaling in other diseases affecting cancer patients, including obesity, diabetes, and inflammation.

细胞毒性化学疗法引起的副作用，包括恶心和呕吐，施加严重的 癌症患者的身体和情感负担，这可能会限制使用剂量加密治疗 癌症治疗。尽管这些不良反应的确切机制仍然晦涩，但电流 理论表明，来自胃肠道（GI）的迷走神经信号起着至关重要的作用。直到 现在，无法测试在这些中定义的迷走神经传播信号的功能 对化学疗法的反应是因为外周神经元无法选择性地，可逆 沉默或激活；光遗传学方法可能会消除此障碍。在这里，我们建议 使用小型动物模型进行发育测试（Musk Shrew）作为评估GI调制的平台 迷走信号传导。与啮齿动物不同，麝香（小鼠大小的哺乳动物）具有呕吐的反射和 是雪貂，猫和狗的有效替代品，用于研究化学疗法诱导的发育作用。 我们的中心假设指出，迷走神经神经元可以光遗传控制 产生呕吐或抑制化学疗法诱导的呕吐。我们计划通过 追求两个具体的目的：（1）测试含有光敏的病毒载体的运输特异性 Opsins，Halorhopopsin（用于抑制）和ChannelRhopopsin-2（用于激发）gi迷走神经传入 人口； （2）确定迷走神经信号传导光学调制对呕吐的影响。腺 相关病毒（AAVS）将被注入特定的胃区域，以感染迷走神经亚 人群。 AAVS还将包含荧光记者，以允许对亚的组织学检查 一组nodose神经神经元。施加在AAV负载的迷走神经纤维上的特定波长将 用于在我们既定的体内刺激和抑制化学疗法（由化学疗法产生） 电生理准备。这些实验将确认使用光遗传学方法 调节迷走神经传播。该项目的结果在控制中很有价值 测试催吐机制；同样，可能采用光遗传学方法来评估 其他影响癌症患者的疾病中的迷走神经信号，包括肥胖，糖尿病和 炎。