Animal models are necessary to investigate the pathogenic features underlying motor neuron degeneration and for therapeutic development in amyotrophic lateral sclerosis（ALS）. Measures of model validity allow for a c...Animal models are necessary to investigate the pathogenic features underlying motor neuron degeneration and for therapeutic development in amyotrophic lateral sclerosis（ALS）. Measures of model validity allow for a critical interpretation of results from each model and caution from over-interpretation of experimental models. Face and construct validity refer to the similarity in phenotype and the proposed causal factor to the human disease, respectively. More recently developed models are restricted by limited phenotype characterization, yet new models hold promise for novel disease insights, thus highlighting their importance. In this article, we evaluate the features of face and construct validity of our new zebrafish model of environmentally-induced motor neuron degeneration and discuss this in the context of current environmental and genetic ALS models, including C9 orf72, mutant Cu/Zn superoxide dismutase 1 and TAR DNA-binding protein 43 mouse and zebrafish models. In this mini-review, we discuss the pros and cons to validity criteria in each model. Our zebrafish model of environmentally-induced motor neuron degeneration displays convincing features of face validity with many hallmarks of ALS-like features, and weakness in construct validity. However, the value of this model may lie in its potential to be more representative of the pathogenic features underlying sporadic ALS cases, where environmental factors may be more likely to be involved in disease etiology than single dominant gene mutations. It may be necessary to compare findings between different strains and species modeling specific genes or environmental factors to confirm findings from ALS animal models and tease out arbitrary strain-and overexpression-specific effects.展开更多
氨基糖苷类抗生素因其抗菌谱广、抗菌能力强,半个多世纪以来一直是临床上常用的抗菌素之一。但氨基糖苷类抗生素具有很强的耳毒和肾毒作用,在药物致聋因素中排在首位。本研究以庆大霉素(gentamycin)、新霉素(neomycin)、链霉素(streptom...氨基糖苷类抗生素因其抗菌谱广、抗菌能力强,半个多世纪以来一直是临床上常用的抗菌素之一。但氨基糖苷类抗生素具有很强的耳毒和肾毒作用,在药物致聋因素中排在首位。本研究以庆大霉素(gentamycin)、新霉素(neomycin)、链霉素(streptomycin)等3种氨基糖苷类抗生素为代表性药物,研究其对斑马鱼胚胎发育的毒性作用和对幼体毛细胞的损伤作用,并探索了该损伤与听觉相关基因之间的联系。结果显示:①3种药物的致死作用都具有明显的浓度依赖性,其致死作用的强弱顺序为链霉素>新霉素>庆大霉素;②3种药物处理的5 dpf(day past fertilization)幼体出现身体失衡及体位异常,以及耳囊结构的异常变化;③毛细胞染色实验可观察到,3种药物作用的毛细胞和神经丘均出现明显的损伤和数量减少;④与听觉器官发育相关的基因eya1、val、otx2、dlx6a均随3种抗生素药物浓度的升高,出现差异性的表达水平下调。本研究首次探索了这3种耳毒性氨基糖苷类抗生素处理与斑马鱼听囊结构和听觉基因表达的相关性;并证明利用斑马鱼建立简便、准确、直观、快速地检测药物耳毒性的模型和检测方法的可行性。展开更多
基金supported by a grant from Estate of Luther Allyn Shourds Dean,No.20R17162(to CAS)
文摘Animal models are necessary to investigate the pathogenic features underlying motor neuron degeneration and for therapeutic development in amyotrophic lateral sclerosis（ALS）. Measures of model validity allow for a critical interpretation of results from each model and caution from over-interpretation of experimental models. Face and construct validity refer to the similarity in phenotype and the proposed causal factor to the human disease, respectively. More recently developed models are restricted by limited phenotype characterization, yet new models hold promise for novel disease insights, thus highlighting their importance. In this article, we evaluate the features of face and construct validity of our new zebrafish model of environmentally-induced motor neuron degeneration and discuss this in the context of current environmental and genetic ALS models, including C9 orf72, mutant Cu/Zn superoxide dismutase 1 and TAR DNA-binding protein 43 mouse and zebrafish models. In this mini-review, we discuss the pros and cons to validity criteria in each model. Our zebrafish model of environmentally-induced motor neuron degeneration displays convincing features of face validity with many hallmarks of ALS-like features, and weakness in construct validity. However, the value of this model may lie in its potential to be more representative of the pathogenic features underlying sporadic ALS cases, where environmental factors may be more likely to be involved in disease etiology than single dominant gene mutations. It may be necessary to compare findings between different strains and species modeling specific genes or environmental factors to confirm findings from ALS animal models and tease out arbitrary strain-and overexpression-specific effects.
文摘氨基糖苷类抗生素因其抗菌谱广、抗菌能力强,半个多世纪以来一直是临床上常用的抗菌素之一。但氨基糖苷类抗生素具有很强的耳毒和肾毒作用,在药物致聋因素中排在首位。本研究以庆大霉素(gentamycin)、新霉素(neomycin)、链霉素(streptomycin)等3种氨基糖苷类抗生素为代表性药物,研究其对斑马鱼胚胎发育的毒性作用和对幼体毛细胞的损伤作用,并探索了该损伤与听觉相关基因之间的联系。结果显示:①3种药物的致死作用都具有明显的浓度依赖性,其致死作用的强弱顺序为链霉素>新霉素>庆大霉素;②3种药物处理的5 dpf(day past fertilization)幼体出现身体失衡及体位异常,以及耳囊结构的异常变化;③毛细胞染色实验可观察到,3种药物作用的毛细胞和神经丘均出现明显的损伤和数量减少;④与听觉器官发育相关的基因eya1、val、otx2、dlx6a均随3种抗生素药物浓度的升高,出现差异性的表达水平下调。本研究首次探索了这3种耳毒性氨基糖苷类抗生素处理与斑马鱼听囊结构和听觉基因表达的相关性;并证明利用斑马鱼建立简便、准确、直观、快速地检测药物耳毒性的模型和检测方法的可行性。
