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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

基本信息

批准号：
9348619
负责人：
Charles Christopher Horn
金额：
$ 7.78万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-07 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9348619
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 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 Predisposition to Disease Goals Halorhodopsins Histologic Horns Immunohistochemistry Inflammation Injectable 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 experimental study ganglion cell gastrointestinal improved in vivo innovation member minimally invasive optogenetics receptive field receptor response theories thoracic pressure tool transmission process

项目摘要

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，造成严重的癌症患者的身体和情感负担，这可能限制剂量密集治疗的使用癌症治疗。虽然这些不良反应的确切机制仍然不清楚，但目前理论认为来自胃肠（GI）道的迷走神经感觉信号起关键作用。直到现在，已经不可能在这些动物中测试定义的迷走传入群体信号传导的功能。因为外周神经元不能选择性地，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，我们建议使用呕吐试验的小动物模型（麝香鼩）作为评估GI调节的平台迷走神经信号与啮齿类动物不同，麝香鼩（一种老鼠大小的哺乳动物）有呕吐反射，是研究化疗诱导呕吐的雪貂、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遗传学控制，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验证这一假设追求两个具体目标：（1）测试含有光敏的病毒载体的转运特异性胃肠道迷走神经传入纤维中的视蛋白、盐视紫红质（用于抑制）和通道视紫红质-2（用于兴奋）群体;和（2）确定迷走神经信号传导的光学调制对呕吐的影响。腺- 相关病毒（AAV）将被注射到特定的胃区域，以感染迷走神经亚细胞，人口。AAV还将含有荧光报告基因以允许对亚细胞进行组织学检查。成组的结状神经节神经元。应用于AAV负载迷走神经纤维的特定波长的光将用于刺激和抑制呕吐（由化疗产生）在我们建立的体内电生理学准备这些实验将证实光遗传学方法的使用，调节迷走神经感觉传递。本课题的研究成果对控制和管理具有一定的参考价值。测试呕吐机制;类似地，光遗传学方法可用于评估在影响癌症患者的其他疾病中的迷走神经信号传导，包括肥胖症、糖尿病和炎症