There is a great need to create novel approaches to drug discovery and development to optimize this critical process, as well as to create powerful pathway modulation tools for systems biology. The University of Pittsburgh Drug Discovery Institute (UPDDI) provides an environment in which novel technical approaches can be rapidly integrated into the drug discovery pipeline, along with existing methods.
Cell and Engineered Model Tissue Screening:
The staff of the UPDDI are highly experienced in cell analysis, from very high throughput whole well screens, to high throughput High Content Screening (HCS) and single cell multiplexed screens. The UPDDI maintains multiple HCS platforms, confocal and wide field, fixed endpoint and live cell, to automate the capture and analysis of fluorescence images of millions of individual cells exposed to thousands of compounds on a daily basis. Through optimal selection of appropriate cells, probes, antibodies, fluorescent protein fusions, biosensors and environmentally sensitive probes, the staff of the UPDDI can apply HCS technology to many drug target classes and phenotypic screens. HCS, whether confocal or wide field, is one of the most powerful tools available to investigate molecular mechanisms in the context of the cell and small experimental animal systems.
The zebrafish embryo is an ideal animal system for in vivo HCS. We apply HCS to identify small molecules that modulate pathways in zebrafish embryos. The 1-day old embryo is approximately 1mm in diameter and can be easily arrayed into 96-well plates for screening. During the first day of development, embryos are transparent with most of the major organs present, thus enabling visualization of tissue formation during embryogenesis, and organ specific measurements.
High Content and High Throughput Screening:
One option for QSP is using an in silico chemogenomics approach inferring the molecular mechanisms of a phenotype of interest based on a collection of chemicals identified through phenotypic screening. The UPDDI Screening Facility, located on the ninth floor in the Biomedical Science Tower (BST), is set up to run HCS phenotypic screens on annotated compound libraries primarily for this purpose, though it can also provide collaborators with the ability to run HCS and non-phenotypic screens on hundreds to thousands of compounds from other libraries. The facility is equipped with a number of automated, robotic platforms and a variety of detection instruments enabling the running of every kind of assay. The UPDDI faculty and staff, which includes several members formerly in the pharma industry, are well experienced in designing, implementing, and analyzing HCS and phenotypic assays and screens.