Advancing Whole-Organism Screening for Chemical Modifiers of the Brain

描述（由申请人提供）：斑马鱼在胚胎和幼虫阶段的大规模筛选和透明性质的适用性使其成为在完整生物体中进行小分子筛选的有吸引力的系统，目的是鉴定治疗化合物并了解生物学机制。DA神经元在人类帕金森病（PD）中退化，帕金森病是一种目前无法治愈的破坏性神经退行性疾病。斑马鱼作为一种能够产生大量透明胚胎和幼虫的脊椎动物模式生物，非常适合发现可以调节DA神经元发育、维持或再生的小分子。然而，基于整个生物体的化学筛选的关键限制是低通量和低分辨率。在该提案中，我们将通过使用我们已经建立的DA神经元测定，开发并整合快速高分辨率全生物体成像与改进的基于微流体的技术，来推进全生物体筛选。如果成功，该平台将彻底改变整个生物体的筛选能力，并导致新的小分子化合物，可以改变CNS的发育和功能，并为PD的潜在治疗提供线索。

DESCRIPTION (provided by applicant): The suitability for large-scale screening and the transparent nature during embryonic and larval stages make zebrafish an attractive system for small molecule screening in an intact organism, with aims both to identify therapeutic compounds and to understand biological mechanisms. DA neurons degenerate in human Parkinson's disease (PD), a devastating neurodegenerative disorder for which there is currently no cure. Zebrafish, as a prominent vertebrate model organism with the ability to produce a large number of transparent embryos and larvae, is ideally suited for discovering small molecules that can regulate the development, maintenance, or regeneration of DA neurons. However, key limitations with whole organism-based chemical screening is low throughput and low resolution. In this proposal, we will advance whole organism screening by developing and integrating fast speed high-resolution whole-organism imaging with an improved microfluidics- based technology, using the DA neuron assay that we have already established. If successful, this platform will revolutionize the whole-organism screening capability and lead to novel small molecule compounds that can modify CNS development and function and provide leads for potential treatment of PD.