High-throughput screening of small molecule and siRNA libraries
Recent advances in biomedical sciences have drastically accelerated the discovery of the molecular and cellular bases of intractable human diseases. One of our major challenges today is how to translate the newly acquired knowledge of biological components and mechanisms into new medicines for disease prevention and treatment. High-throughput screening, the use of highly automated in vitro assays for assessing the activity of libraries of small molecules or siRNA reagents, has become a dominant technology for identifying both the genes and pathways that mediate disease states and novel compounds that modulate these pathways. The Integrated Screening Core (ISC) aims to facilitate this translation process by providing Mount Sinai researchers with the technical resources and expertise needed to carry out high-throughput screens using either cell- or target-based (cell-free biochemical) assays. These screens can be carried out using small molecule or siRNA libraries curated by the ISC or with custom libraries developed by Mount Sinai researchers. Additionally, the ISC staff provides researchers with extensive support in the development, automation and execution of their screens.
The ISC provides Mount Sinai researchers with critical resources for developing and executing high-throughput screens based on assays developed in the researcher's laboratory, including:
- Laboratory automation: robotic liquid handlers, plate readers and microscope systems
- Small molecule and siRNA libraries
- Database resources for storing and analyzing results
The ISC maintains a variety of technical resources for executing high-throughput assays, including automated liquid handlers (Perkin Elmer JANUS Varispan and MDT; TECAN EVO 150 & 200), plate readers (Perkin Elmer EnVision; TECAN Sapphire and Genios) and high-content microscopes (Molecular Devices ImageXpress Ultra). Together, these tools permit facility users to develop both medium- and high-throughput screens based on the best currently-available detection methods.
Small molecule: The ISC provides research investigators at Mount Sinai access to small molecule chemical compounds that can be used as tools to advance discovery basic and translational research of human biology and disease and in drug discovery. The chemical screening resources at the ISC include diverse chemical libraries of about 115,000 small-molecule chemical compounds selected based on their drug-like properties as defined by the Lipinski's "Rule of Five". Following the identification of a 'hit' from a primary screen, assistance with the synthesis of optimized libraries of structurally-related compounds is available through the ETI Medicinal Chemistry Program.
RNAi: The ISC provides facility users with access to genome-wide siRNA libraries (human & mouse; siGenome, Dharmacon/Thermo-Fisher) for use in cell-based screens carried out in the facility.
The ISC maintains the database infrastructure necessary to support both basic data mining and the advanced informatics approaches needed to handle the large data sets that are produced by high-throughput and high-content screens. Assistance with the use of in-house data analysis tools is available from the ISC staff. Structural modeling and virtual optimization of small molecule-target interactions is available through the ETI Molecular Informatics Core.
High-throughput screening offers a number of challenges that are not present in a typical laboratory setting. The high degree of laboratory automation requires a trained staff to maintain and program individual instruments to ensure accurate and reproducible results. Additionally, assay design can have a significant impact on the overall cost of these large-scale projects. The ISC staff assists researchers with assay development and execution, collaborating at all stages of project development, execution and analysis.
The ISC is designed to function both as an intellectual base and a core research facility for Mount Sinai faculty in their goal to develop novel treatments for disease. The ISC provides the intellectual capital, collaborative opportunities and access to state-of-the-art technologies in chemical biology and participates in the training of future research scientists and health care practitioners.
For more information regarding ISC functions and services, please contact Dan Felsenfeld, PhD, at email@example.com.
Louise Lammers, PhD
Associate Director Operations
Experimental Therapeutics Institute
Icahn School of Medicine at Mount Sinai
One Gustave L. Levy Place, Box 1608
1468 Madison Avenue
New York, NY 10029-6574