Parallel Genomic and Chemical Screens to Identify Both Therapeutic Targets and Inhibitors of These Targets in the Treatment of Neurofibromatosis

摘要

In model systems, such as Drosophila, high-throughput genetic and chemical screens are powerful tools to elucidate the components and inhibitors of signaling pathways. The success of these screens is dependent on the development of experimental assays which serve as readouts of pathway activity. However, to date no such assay has been developed to monitor the activity of Nf1 or Nf2. Here we describe the development of a novel technology that can be used to rigorously quantify and analyze single-cell morphology in an automated fashion. As a proof-of concept we have analyzed morphological data derived from 249 different conditions, and defined phenoclusters of functionally related genes. We observe that Nf1 and Nf2 are members of distinct phenoclusters, and that other genes in these clusters may be highly relevant to understanding role of Nf1 and Nf2 in promoting disease. With the successful development of methods to determine quantitative phenotypic profiles of cells, performing screens for genetic or chemical modifiers of Nf1 or Nf2 is now feasible.