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、呕吐和厌食症是可列举的治疗药物、疾病和 疾病治疗。一个极端的例子是呕吐化疗(EC)引起的恶心和 呕吐(CINV)和能量平衡失调，破坏生活质量和避免治疗 坚持不懈。值得注意的是，CINV和能量平衡失调的完全控制尚未实现， 尽管据估计，每年有65万名癌症患者接受化疗。神经学 通过化疗产生CINV和能量平衡失调的回路仍然难以捉摸。 最近的数据发现，EC激活的孤束核(NTS)神经元向外侧投射的回路 臂旁核(LPBN)和EC激活的投射到中央核的lPBN神经元。 大鼠杏仁核(CEA)。进一步的结果表明，CEA谷氨酸受体信号，可能通过 LPBN→CEA投影，是EC诱导的PicA充分表达所必需的(一个经过验证的啮齿动物模型 恶心/不适)、食欲不振和体重减轻。尽管这些数据开始勾勒出中枢神经系统部位的环路 EC引起的萎靡不振和厌食症是由哪些因素引起的，该回路的重要细节尚不清楚。 具体地说，功能相关性、神经化学表型、调节输入和靶投射 必须直接对这些后脑-前脑神经种群进行调查，以发现 CINV的治疗与能量平衡失调。为此，该提案中的创新方法 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 CINV和能量失调中的特定类型神经元群体，[2]检查 EC激活的CEA神经元的神经肽/信号表型(S)和突触后靶点，以及[3]研究 中枢GLP-1信号在慢性静脉曲张时NTS、1PBN和CEA中的调节作用及能量失调。 拟议的实验将使用不呕吐和呕吐的实验动物模型，并将其与 最大限度地发挥这部作品的翻译潜力。总体而言，这些研究将扩大我们对 通过揭示细胞因子介导化疗所致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 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与能量平衡失调的治疗。