Zebrafish Muscular Dystrophy Model for Drug Screening

描述（由申请人提供）：该SBIR提案旨在开发和验证斑马鱼模型，用于筛选缓解肌肉萎缩症（MD）相关症状的药物。MD由几种临床和遗传异质性疾病组成，其特征是控制运动的骨骼肌或随意肌的进行性无力和变性。在某些形式的MD中，心肌和一些不随意肌也会受到影响。MD可以发生在任何年龄。杜氏病是影响儿童的最常见的MD形式，而肌强直性是影响成人的最常见形式。虽然对MD的分子基础的认识有了很大的提高，但目前还没有有效的治疗方法。治疗策略的开发是生物制药行业的一个主要焦点。小鼠和犬类模型在阐明MD疾病机制和评估潜在治疗策略方面很有用，但这两种模型都不能用于大规模遗传筛选或快速药物筛选。虽然已经开发出更简单的体内模型系统，如秀丽隐杆线虫（dys1），但这些无脊椎动物模型相对较差地预测了人类的功效和毒性，因为它们的代谢和生理与人类非常不同。需要一种结合无脊椎动物和小鼠系统优点的新动物模型来简化药物发现过程。这种斑马鱼模型将有助于筛选潜在的治疗方法，减轻与肌肉萎缩症相关的症状，并简化药物开发时间表。

DESCRIPTION (provided by applicant): This SBIR proposal aims to develop and validate a zebrafish model for screening drugs that mitigate symptoms associated with muscular dystrophy (MD). MD is comprised of several clinically and genetically heterogeneous disorders characterized by progressive weakness and degeneration of the skeletal or voluntary muscles which control movement. In some forms of MD, heart muscles and some involuntary muscles are also affected. MD can occur at any age. Duchenne is the most common form of MD affecting children, whereas myotonic is the most common form affecting adults. Although there has been tremendous improvement in the understanding of the molecular basis of MD, no effective treatment is currently available. Development of therapeutic strategies is a major focus of the biopharmaceutical industry. Murine and canine models have been useful in elucidating MD disease mechanisms and assessing potential therapeutic strategies, but neither model can be used for large scale genetic screens or for rapid drug screening. Although simpler in vivo model systems such as C. elegans (dys-1) have been developed, these invertebrate models are relatively poor predictors of efficacy and toxicity in humans because their metabolism and physiology are very different from those of humans. A new animal model that combines the advantages of invertebrate and mouse systems is needed to streamline the drug discovery process. This zebrafish model will facilitate screening of potential therapeutics that mitigate symptoms associated with muscular dystrophy and streamline the drug development timeline.