神经退行性疾病动物模型的建立与应用

The establishment and application of animal models for neurodegenerative diseases

神经退行性疾病的日益增长对家庭和社会造成沉重的负担,寻找有效的预防和治疗方法,已经成为全球公共卫生的重要议题.动物模型在研究神经退行性疾病中发挥着至关重要的作用,为深入理解这些疾病的病理机制、开发新的诊疗策略提供了基础数据.本文阐述了构建常见神经退行性疾病动物模型的方法,包括阿尔茨海默病、帕金森病和肌萎缩性脊髓侧索硬化症等.这些模型的建立考虑了疾病的遗传背景、病理特征以及进程.传统疾病模型构建方法常常缺乏疾病特异性、表型稳定性和与人类疾病病理进程的一致性.得益于基因修饰技术的发展,如CRISPR/Cas9技术,我们能够更精确地模拟人类神经退行性疾病的病理过程,使得动物模型能够为药物开发和疾病预防策略的探索提供重要工具.本文还探讨了新的动物模型开发进展,这对于深入理解疾病的发病机制、研究环境因素和基因-环境相互作用、筛选新的药物和开发新的治疗策略至关重要.虽然目前的模型还无法完全反映人类疾病的复杂性,我们有理由相信,这些限制将会得到改善,并展望了基因编辑技术可能改变神经退行性疾病研究的未来.

The increasing prevalence of neurodegenerative diseases constitutes a significant challenge to public health systems globally.Consequently,the quest for efficacious preventive and therapeutic strategies has assumed center stage in public health discourse.Animal models serve as indispensable instruments in neurodegenerative disease research,offering foundational data that inform our understanding of the pathological mechanisms and contribute to the development of novel therapeutic paradigms.This manuscript delineates the methodologies for constructing animal models germane to prevalent neurodegenerative conditions such as Alzheimer’s Disease,Parkinson’s Disease,and Amyotrophic Lateral Sclerosis.The establishment of these models incorporates factors like genetic etiology,pathological signatures,and the temporal course of disease progression.Traditional techniques in model development frequently exhibit shortcomings in disease specificity,phenotypic stability,and alignment with the pathological evolution of human ailments.However,advancements in gene-editing technologies,notably CRISPR/Cas9,facilitate the emulation of human neurodegenerative disease pathologies with increased precision.This augments the relevance of animal models as instrumental tools in pharmaceutical development and the formulation of disease prevention strategies.In addition to conventional neurodegenerative animal models,the manuscript explores advancements in innovative models including chemical induction models,human brain tissue transplantation models,spontaneous models,and accelerated aging models.A focal point of the discourse is the transformative impact of gene-editing technologies on animal model development,with emphasis on the theoretical foundations and methodologies for creating polygenic breeding models and genetically diverse,gene-edited models.1.Key gene-editing technologies applied in the domain of animal model creation encompass gene knock-in/knock-out,RNA interference(RNAi),and CRISPR/Cas9.Gene knock-in entails the integration of a target gene into a predetermined genomic location,while gene knock-out involves the excision of a specific gene,either entirely or partially.Both processes are predicated on homologous recombination,leveraging the innate capability of DNA molecules for homologous pairing and exchange to insert the target gene at precise chromosomal loci.2.Complex human diseases frequently involve an array of genes or quantitative trait loci(QTL),each exerting a modest impact on the disease phenotype.When multiple QTLs are inherited,disease manifestation or predisposition may ensue.The advancement of mouse models for Alzheimer’s Disease epitomizes this intricate multi-gene or multi-locus modification process.As stronger genetic drivers and their combinations are identified,the selection and arrangement of divergent mouse strains can refine these models further.3.The utility of genetically diverse gene-edited animal models lies in their ability to replicate human genetic variability by exploiting the phenotypic differences inherent in mice with assorted genetic backgrounds.The integration of gene-edited animal models into neurodegenerative disease research enhances our mechanistic understanding of these conditions.The manuscript elucidates emergent research avenues in gene-edited animal models,including the capabilities of polygenic models to emulate intricate disease states and the evolving role of comorbidity models.These tools are pivotal for a comprehensive understanding of disease pathogenesis,the elucidation of environmental and genetic interactions,the screening of pharmaceutical candidates,and the conception of innovative therapeutic interventions.Although existing models fail to capture the full complexity of human diseases,there is a rational expectation that ongoing technological innovations will ameliorate these limitations,thereby influencing the future trajectory of neurodegenerative disease research.