Neural mechanisms of nausea, vomiting, and energy balance dysregulation in animal models

动物模型中恶心、呕吐和能量平衡失调的神经机制

• 批准号: 9895765
• 负责人: Bart C DE JONGHE
• 金额: $ 36.19万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895765
• 关键词: Address; Amygdaloid structure; Animal Model; Anorexia; Antiemetics; Attenuated; Body Weight decreased; Cancer Patient; Cell Nucleus; Chemicals; Cisplatin; Clinic; Data; Development; Disease; Face; Foundations; GLP-I receptor; Glutamate Receptor; Glutamates; Goals; Immunohistochemistry; Incidence; Intake; Investigation; Knowledge; Laboratory Animal Models; Lateral; Malaise; Mediating; Mediation; Modeling; Mus; Nausea; Nausea and Vomiting; Neurons; Neuropeptides; Neurosciences; Operative Surgical Procedures; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phenotype; Pica Disease; Population; Prosencephalon; Public Health; Publications; Quality of life; Rattus; Receptor Signaling; Research; Rodent Model; Role; Shrews; Signal Transduction; Site; Structure of terminal stria nuclei of preoptic region; Symptoms; Synapses; Systems Development; Techniques; Technology; Therapeutic; Viral; Vomiting; Work; cell type; chemotherapy; designer receptors exclusively activated by designer drugs; energy balance; experimental study; glucagon-like peptide 1; hindbrain; improved; innovation; knock-down; mouse genetics; neural circuit; neurochemistry; neuromechanism; novel; parabrachial nucleus; prophylactic; recruit; relating to nervous system; side effect; treatment adherence; virtual

Project Summary Nausea, vomiting, and anorexia are common side effects of enumerable therapeutic drugs, diseases, and disease treatments. An extreme example of this is emetogenic chemotherapy (EC)-induced nausea and vomiting (CINV) and energy balance dysregulation, which devastate quality of life and obviate treatment adherence. Strikingly, complete control of CINV and energy balance dysregulation has not been achieved, despite the fact that an estimated 650,000 cancer patients undergo chemotherapy each year. The neural circuits that are engaged by chemotherapy to produce CINV and energy balance dysregulation remain elusive. Recent data identify a circuit of EC-activated nucleus tractus solitarius (NTS) neurons that project to the lateral parabrachial nucleus (lPBN), and EC-activated lPBN neurons that project to the central nucleus of the amygdala (CeA) in the rat. Further results indicate that CeA glutamate receptor signaling, potentially via the lPBN→CeA projection, is necessary for the full expression of EC-induced pica (a validated rodent model of nausea/malaise), anorexia, and weight loss. Though these data begin to outline a circuit of CNS sites through which EC-induced malaise and anorexia are mediated, important details of the circuit remain unknown. Specifically, the functional relevance, neurochemical phenotypes, modulatory inputs, and target projections of these hindbrain-forebrain neural populations must be directly investigated to uncover novel targets for the treatment of CINV and energy balance dysregulation. To this end, the innovative approaches in this proposal combine state-of-the-art neuroscience techniques to [1] investigate the functional role of projection- and cell type-specific neuron populations in the mediation of CINV and energy dysregulation, [2] examine the neuropeptide/signaling phenotype(s) and post-synaptic targets of EC-activated CeA neurons, and [3] examine the modulatory role of central GLP-1 signaling in the NTS, lPBN, and CeA in CINV and energy dysregulation. The proposed experiments will use and compare non-vomiting and vomiting laboratory animal models to maximize translational potential of this work. Overall, these studies will expand our understanding of the mechanisms mediating chemotherapy-induced malaise and energy balance dysregulation by revealing the neurocircuitry and chemical signals that produce these undesirable side effects. Additionally, results will identify new target neuron populations and/or neurochemical/peptide systems for the development of novel treatments of CINV and energy balance dysregulation.

项目概要 恶心、呕吐和厌食是多种治疗药物、疾病和疾病的常见副作用。 一个极端的例子是致吐化疗（EC）引起的恶心和呕吐。 呕吐 (CINV) 和能量平衡失调，会破坏生活质量并阻碍治疗 引人注目的是，CINV 和能量平衡失调的完全控制尚未实现。 尽管每年估计有 650,000 名癌症患者接受化疗。 化疗参与产生 CINV 和能量平衡失调的回路仍然难以捉摸。 最近的数据确定了 EC 激活的孤束核 (NTS) 神经元的回路，该神经元投射到外侧 臂旁核 (lPBN) 和 EC 激活的 lPBN 神经元投射到臂旁核的中央核 进一步的结果表明，CeA 谷氨酸受体信号传导可能通过 lPBN→CeA 投影，对于 EC 诱导的异食癖的完全表达是必要的（一种经过验证的啮齿动物模型） 尽管这些数据开始勾勒出中枢神经系统站点的回路。 EC 引起的不适和厌食症是由哪种机制介导的，但该回路的重要细节仍不清楚。 具体来说，功能相关性、神经化学表型、调节输入和目标预测 必须直接研究这些后脑-前脑神经群体，以发现新的目标 治疗 CINV 和能量平衡失调 为此，本提案提出了创新方法。 结合最先进的神经科学技术 [1] 研究投射和细胞的功能作用 类型特异性神经元群在 CINV 和能量失调介导中的作用，[2] 检查 神经肽/信号传导表型和 EC 激活的 CeA 神经元的突触后靶标，并 [3] 检查 NTS、lPBN 和 CeA 中的中央 GLP-1 信号传导在 CINV 和能量失调中的调节作用。 拟议的实验将使用并比较非呕吐和呕吐实验动物模型 总的来说，这些研究将扩大我们对这项工作的理解。 通过揭示介导化疗引起的不适和能量平衡失调的机制 此外，产生这些不良副作用的神经回路和化学信号也会产生影响。 确定新的目标神经元群体和/或神经化学/肽系统以开发新的 CINV 和能量平衡失调的治疗。