Advancing Whole-Organism Screening for Chemical Modifiers of the Brain

描述(申请人提供)：适合大规模筛选和胚胎和幼体阶段的透明性质使斑马鱼成为在完整生物体中进行小分子筛选的一个有吸引力的系统，目的是识别治疗化合物和了解生物机制。人类帕金森氏病(PD)中DA神经元变性，这是一种毁灭性的神经退行性疾病，目前尚无治愈方法。斑马鱼作为一种重要的脊椎动物模式生物，具有产生大量透明胚胎和幼虫的能力，非常适合发现调节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。在这个方案中，我们将利用我们已经建立的DA神经元检测技术，通过开发和集成快速高分辨率全生物成像和改进的基于微流体的技术来推进全生物筛查。如果成功，该平台将彻底改变整个生物体的筛选能力，并导致新型小分子化合物的出现，这些小分子化合物可以改变中枢神经系统的发育和功能，并为潜在的帕金森病治疗提供指导。

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.