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.

Public Health Relevance

This application aims to significantly speed up the identification of small molecule drug-like compounds that can regulate the development maintenance and regeneration of dopaminergic (DA) neurons. Since DA neurons degenerate in Parkinson's disease, our proposed studies are likely to have a significant impact on discovering therapeutic compounds for treating this devastating neurodegenerative disorder.

National Institute of Health (NIH)
Exploratory/Developmental Grants (R21)
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Sieber, Beth-Anne
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University of California San Francisco
Schools of Pharmacy
San Francisco
United States
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Liu, Harrison; Chen, Steven; Huang, Kevin et al. (2016) A High-Content Larval Zebrafish Brain Imaging Method for Small Molecule Drug Discovery. PLoS One 11:e0164645
Gehrke, Stephan; Wu, Zhihao; Klinkenberg, Michael et al. (2015) PINK1 and Parkin control localized translation of respiratory chain component mRNAs on mitochondria outer membrane. Cell Metab 21:95-108
McGorty, Ryan; Liu, Harrison; Kamiyama, Daichi et al. (2015) Open-top selective plane illumination microscope for conventionally mounted specimens. Opt Express 23:16142-53