Fast Drug Screening via Mechanics of Tissue Constructs

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DESCRIPTION (provided by applicant): The availability of libraries containing large numbers of chemical compounds potentially applicable as drugs poses the challenge of screening these compounds for their pharmaceutical utility. High throughput screening methods that measure chemical interactions between the candidate compound and a selected target molecule such as a receptor can screen compounds at high speed, but provide no information about the biological response of cells. As a result many compounds are selected that are inactive biologically or are toxic. Therefore, it is important to have rapid screening methods based on cellular biological responses. The major goal of this proposal is to develop and validate a prototype device that screens compounds based on cellular responses that produce mechanical changes in biological tissue constructs. This approach measures changes of contractile force and stiffness of miniaturized tissue constructs in a format suitable for rapid screening. This approach is advantageous in several respects: . the assay is based on the measurement of a cellular contractile response that is activated by many biologically important signaling pathways;  the assay can be carried out rapidly and in a parallel format on many samples; . the assay can be carried out with miniaturized samples to conserve precious materials; . the assay provides quantitative information about cellular and extracellular responses to test compounds; . tissue constructs can be assembled to provide models for specific disease conditions, e.g., elevated contractility of vascular smooth muscle cells in hypertension or fibrosis and cardiovascular remodeling responsible for congestive heart failure or diastolic dysfunction and for scar formation. The specific aims are to optimize a prototype device for measuring mechanical responses of minitissue constructs, to validate the device by comparison with measurements of previously studied tissue constructs and then to demonstrate the utility of this device in a screen for compounds that can regulate blood pressure by reducing contractile force exerted by vascular smooth muscle cells.