Irizarry Kristopher J L, Zhong Weixia, Sun Yina, Kronmiller Brent A, Darmani Nissar A
College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA, United States.
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States.
Front Genet. 2023 Feb 14;14:975087. doi: 10.3389/fgene.2023.975087. eCollection 2023.
The least shrew is among the subset of animals that are capable of vomiting and therefore serves as a valuable research model for investigating the biochemistry, molecular biology, pharmacology, and genomics of emesis. Both nausea and vomiting are associated with a variety of illnesses (bacterial/viral infections, bulimia, exposure to toxins, gall bladder disease), conditions (pregnancy, motion sickness, emotional stress, overeating) and reactions to drugs (chemotherapeutics, opiates). The severe discomfort and intense fear associated with the stressful symptoms of nausea and emesis are the major reason for patient non-compliance when being treated with cancer chemotherapeutics. Increased understanding of the physiology, pharmacology and pathophysiology underlying vomiting and nausea can accelerate progress for developing new antiemetics. As a major animal model for emesis, expanding genomic knowledge associated with emesis in the least shrew will further enhance the laboratory utility of this model. A key question is which genes mediate emesis, and are they expressed in response to emetics/antiemetics. To elucidate the mediators of emesis, in particular emetic receptors, their downstream signaling pathways, as well as the shared emetic signals, we carried out an RNA sequencing study focused on the central and peripheral emetic loci, the brainstem and gut. Thus, we sequenced RNA extracted from brainstem and gut tissues from different groups of least shrews treated with either a neurokinin NK receptor selective emetic agonist, GR73632 (5 mg/kg, i.p.), its corresponding selective antagonist netupitant (5 mg/kg, i.p.), a combination of these two agents, their corresponding vehicle-pretreated controls and drug naïve animals. The resulting sequences were processed using a transcriptome assembly and used it to identify orthologs within human, dog, mouse, and ferret gene sets. We compared the least shrew to human and a veterinary species (dog) that may be treated with vomit-inducing chemotherapeutics, and the ferret, another well-established model organism for emesis research. The mouse was included because it does not vomit. In total, we identified a final set of 16,720 least shrew orthologs. We employed comparative genomics analyses as well as gene ontology enrichment, KEGG pathway enrichment and phenotype enrichment to better understand the molecular biology of genes implicated in vomiting.
伶鼬是能够呕吐的动物子集之一，因此是研究呕吐的生物化学、分子生物学、药理学和基因组学的宝贵研究模型。恶心和呕吐都与多种疾病（细菌/病毒感染、贪食症、接触毒素、胆囊疾病）、状况（怀孕、晕动病、情绪压力、暴饮暴食）以及对药物（化疗药物、阿片类药物）的反应有关。与恶心和呕吐的应激症状相关的严重不适和强烈恐惧是癌症化疗患者治疗时不依从的主要原因。对呕吐和恶心背后的生理学、药理学和病理生理学的更多了解可以加速开发新的止吐药的进展。作为呕吐的主要动物模型，扩展与伶鼬呕吐相关的基因组知识将进一步提高该模型在实验室中的效用。一个关键问题是哪些基因介导呕吐，它们是否会因催吐药/止吐药而表达。为了阐明呕吐的介质，特别是催吐受体、它们的下游信号通路以及共同的催吐信号，我们进行了一项RNA测序研究，重点关注中枢和外周催吐位点、脑干和肠道。因此，我们对从不同组的伶鼬的脑干和肠道组织中提取的RNA进行了测序，这些伶鼬分别用神经激肽NK受体选择性催吐激动剂GR73632（5mg/kg，腹腔注射）、其相应的选择性拮抗剂奈妥吡坦（5mg/kg，腹腔注射）、这两种药物的组合、它们相应的载体预处理对照以及未接触过药物的动物进行了处理。使用转录组组装对所得序列进行处理，并用于识别人类、狗、小鼠和雪貂基因集中的直系同源物。我们将伶鼬与人类以及可能接受致吐性化疗药物治疗的兽医物种（狗）以及雪貂（另一种成熟的呕吐研究模型生物）进行了比较。纳入小鼠是因为它不会呕吐。我们总共确定了一组最终的16720个伶鼬直系同源物。我们采用了比较基因组学分析以及基因本体富集、KEGG通路富集和表型富集，以更好地了解与呕吐相关的基因的分子生物学。
