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.

细胞毒性化疗引起的副作用，包括恶心和呕吐，会造成严重的 癌症患者的身体和精神负担，这可以限制使用剂量密集的治疗 癌症治疗。尽管这些不利影响的确切机制仍然不清楚，但目前 理论认为来自胃肠道(GI)的迷走神经感觉信号起着关键作用。直到 现在，已经不可能测试确定的迷走神经传入群体信号在这些区域的功能 对化疗的反应，因为周围神经元不能选择性和可逆地， 沉默或激活；光遗传学方法潜在地消除了这一障碍。在此，我们建议 用小动物模型(麝鼠)作为评估胃肠道调节作用的平台 迷走神经信号。与啮齿动物不同，麝鼠(一种老鼠大小的哺乳动物)有呕吐反射和 是研究化疗引起的呕吐的雪貂、猫和狗的有效替代品。 我们的中心假设是迷走神经传入神经元可以被光基因控制到 产生呕吐或抑制化疗引起的呕吐。我们计划通过以下方式来检验这一假设 追求两个特定目标：(1)测试含有光敏物质的病毒载体运输的特异性 胃肠道迷走神经传入中的视黄素、卤视紫质(抑制)和通道视紫红质-2(兴奋) (2)确定迷走神经信号的光学调制对呕吐的影响。腺体- 相关病毒(AAV)将被注射到特定的胃区域以感染迷走神经亚单位 人口。AAVs还将包含荧光记者，以允许对亚单位进行组织学检查 结状神经节神经元的集合。特定波长的光作用于AAV负载的迷走神经纤维将 被用来刺激和抑制(化疗引起的)体内呕吐 电生理学准备。这些实验将证实使用光遗传方法来 调节迷走神经的感觉传递。该项目的研究成果具有一定的控制和推广价值。 对呕吐机制的测试；类似地，光遗传学方法可用于评估 影响癌症患者的其他疾病中的迷走神经信号，包括肥胖、糖尿病和 发炎。