Coronary Heart Disease (CHD) and stroke are leading causes of death in the United States. The underlying cause of CHD and stroke is atherosclerosis, which is a chronic inflammatory condition of large arteries. A number of genetic and environmental factors are responsible for development of atherosclerosis. Atherosclerosis does not develop uniformly in arteries; hemodynamic characteristics of blood flow that promote laminar shear stress seem to prevent local atherosclerosis. The goal of this project is to develop a novel microfluidics system for performing laminar shear stress assays on vascular endothelium and developing a high-throughput system for atherosclerosis drug discovery. Parallel plate flow chamber has been the most popular method for simulating physiological flow conditions experienced by endothelial cells (ECs). Recently, a commercially produced flow chamber has been introduced that promises to reduce assay volume. However, for high throughput applications, such as screening for new therapeutics, none of the existing technologies are suitable. Genome Data Systems, Inc. (GDS) has developed an innovative and proprietary chip technology called GeneCard that can overcome the challenges of the existing systems. The characteristic feature of GeneCard technology is a modular approach to microfluidics that allows easy introduction of cells, tissues and other solid phase materials into fluidic devices, as well as their easy removal. During this project, GeneCard designs for efficient culture and laminar flow assay of ECs will be investigated. EC cultures will be established on GeneCard devices, and subjected to controlled laminar shear stress. Gene expression profiles of ECs using microarrays will be generated and genes that are regulated by laminar shear stress will be identified. Finally, the ability of known modulators of EC function to reverse gene expression changes induced by laminar shear stress will be investigated. The proposed method provides a user-friendly approach for investigating effects of laminar flow on EC cultures. Smaller number of cells required reduces cost and enables high throughput assays. At the successful completion of the proposed project, GDS will provide complete systems for drug discovery market as well as use the systems for internal R&D efforts and to provide contract screening service.
