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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结