Development of on-chip ultra high-throughput whole-animal assay technologies

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In recent years, the advantages of using the nematode Caenorhabditis elegans as a model system for human disease have become increasingly apparent, culminating in two Nobel Prizes in Physiology and Medicine within the last five years. Existing vertebrate animal models, and the instrumentation incorporated to study them, cannot be utilized for high throughput assays for rapid identification of novel genes, and drug leads. The model organism C. elegans allows in vivo genome-wide assays and high- throughput screens due to the availability of unmatched genetic techniques, its transparency, and the ability to grow it in minute volumes. Yet, since the first publications in early 1960s, little has changed how scientists manipulate this tiny organism manually, as a result of which even simple large-scale assays still take months to years to complete. Importantly, due to the lack of key technologies, several assays either cannot be performed at all or have to be dramatically simplified for high-throughput screens. We propose (1) development of the first on-chip ultra high-throughput whole- animal manipulation technologies for in vivo drug screens and genome-wide discovery of gene functions and interactions by complex on-chip behavioral and biochemical assay strategies; and (2) the first large-scale in vivo study of mechanisms of neural degeneration and regeneration following reproducible injuries using the proposed techniques. The proposed technologies and high-throughput assay strategies can significantly impact discovery of many molecular mechanisms using disease models of small animals.