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，呕吐和厌食症是枚举治疗药物，疾病和 疾病治疗。这是一个极端的例子是促成化疗（EC）引起的恶心和 呕吐（CINV）和能量平衡失调，毁灭生活质量并消除治疗 坚持。令人惊讶的是，尚未完全控制CINV和能量平衡失调， 尽管估计每年有650,000名癌症患者接受化疗。神经 化学疗法参与以产生CINV和能量平衡失调的电路仍然难以捉摸。 最近的数据确定了EC激活的核曲司沿体系的回路 副核（LPBN）和EC激活的LPBN神经元，将其投射到中央核的中心核 大鼠的杏仁核（CEA）。进一步的结果表明，CEA谷氨酸受体信号传导可能通过 LPBN→CEA投影是EC诱导的PICA的全部表达所必需的（经过验证的啮齿动物模型 恶心/不适），厌食和减肥。尽管这些数据开始概述CNS站点的电路 哪些EC引起的不适和厌食症是介导的，电路的重要细节尚不清楚。 具体而言，功能相关性，神经化学表型，调节输入和目标项目 这些后脑前脑神经种群必须直接研究以发现新的目标 CINV和能量平衡失调的处理。为此，本提案中的创新方法 将最新的神经科学技术结合到[1]研究投影和细胞的功能作用 CINV和能量失调的介导中类型特异性神经元种群，[2]检查 EC激活CEA神经元的神经肽/信号表型和突触后靶标，[3]检查 中央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。 提出的实验将使用和比较非呕吐和呕吐实验室动物模型与 最大化这项工作的翻译潜力。总体而言，这些研究将扩大我们对 通过揭示化学疗法引起的不适和能量平衡失调的机制，揭示了 产生这些不良副作用的神经通路和化学信号。此外，结果还将 确定新的靶神经元群体和/或神经化学/肽系统，以开发新颖 CINV和能量平衡失调的处理。