Core C: Molecualr Imaging High Throughput Screening Core (HTS)

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A.3.iii. High Throughput Screening Core (HTS) In response to the NIH Roadmap to Molecular Libraries and Imaging, we have fully established a P50 High Throughput Core. The new Core represents a multi-departmental effort with fiscal support for establishing the Core coming from P50 funds in combination with the Departments of Radiology, Molecular Biology & Pharmacology, and Cell Biology as well as the Howard Hughes Medical Institute. The Dean of Washington University School of Medicine as well as the Director of the Washington University Siteman Cancer Center joined our effort with the commitment of additional funds for further development of the resource. This Core serves as an outstanding on-going example of how our P50 program has leveraged university resources and continues to stimulate interdisciplinary molecular imaging activity throughout the WU campus. We have optimized several robotic protocols and logistical requirements for our first projects in high throughput screening and exciting data are now coming on-line during the summer of 2006. The Core allows for automated screening of cells cultured in 96 or 384 plate formants and can be applied to multiple investigator-initiated molecular imaging applications throughout the university community. The applications include: 1) small molecule screens applied to cells engineered by WU investigators for imaging and therapeutic drug leads. 2) small molecule or peptide screens to identify enzyme inhibitors (directed against high priority proteases, kinases, phosphatases, etc.), or modulators of protein-protein interactions. 3) genome-wide siRNA library screens against kinases, phosphatases and E3-ligases in human cells targeting signal transduction, cell growth or cell death responses. Our first projects are focused on use of the novel split luciferase complementation imaging platform developed in the Molecular Reporter Core for analysis of protein-protein interactions using siRNA libraries against all known expressed human kinases and phosphatases. Knock-down strategies are also being used to explore fusion reporters for bioluminescence readouts of cell cycle regulation, the Notch signaling pathway, and regulation of MDR1 gene expression and other related discovery projects. We will soon be incorporating small molecule libraries from the Chemistry Core. These directly demonstrate the cycle of synergies between the Molecular Reporter Core, the Chemistry Core, the HTS Core and ICMIC R&D Projects.