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.

项目摘要 恶心、呕吐和厌食是可耐受的治疗药物、疾病和药物治疗的常见副作用。 疾病治疗。一个极端的例子是致吐化疗（EC）引起的恶心， 呕吐（CINV）和能量平衡失调，影响生活质量和治疗 坚持。引人注目的是，尚未实现CINV和能量平衡失调的完全控制， 尽管每年估计有650，000名癌症患者接受化疗。神经 化学疗法参与的产生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）神经元投射到外侧的回路 臂旁核（lPBN）和EC激活的lPBN神经元，其投射到臂旁核的中央核。 杏仁核（CeA）。进一步的结果表明，CeA谷氨酸受体信号，可能通过 IPBN →CeA投射，对于EC诱导的异食癖的完全表达是必要的（一种经验证的啮齿动物模型， 恶心/不适）、厌食和体重减轻。尽管这些数据开始勾勒出中枢神经系统位点通过 其中EC诱导的不适和厌食是介导的，电路的重要细节仍然未知。 具体来说，功能相关性，神经化学表型，调节输入，和目标的预测， 必须直接研究这些后脑-前脑神经群，以发现新的靶点， 治疗CINV和能量平衡失调。为此，本提案中的创新方法 联合收割机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体在CINV和能量失调的调解，[2]检查 神经肽/信号传导表型和EC激活的CeA神经元的突触后靶点，并[3]检查 中枢GLP-1信号传导在NTS、lPBN和CeA中的调节作用在CINV和能量失调中。 拟议的实验将使用和比较非呕吐和呕吐的实验室动物模型， 最大限度地发挥这项工作的翻译潜力。总的来说，这些研究将扩大我们对 介导化疗引起的不适和能量平衡失调的机制， 产生这些不良副作用的神经回路和化学信号。此外，结果将 鉴定新的靶神经元群体和/或神经化学/肽系统，用于开发新的神经元细胞。 治疗CINV和能量平衡失调。