High-throughput screening for modulators of cellular contractile force

Chan Young Park; Enhua H. Zhou; Dhananjay Tambe; Bohao Chen; Tera Lavoie; Maria Dowell; Anton Simeonov; David J. Maloney; Aleksandar Marinkovic; Daniel J. Tschumperlin; Stephanie Burger; Matthew Frykenberg; James P. Butler; W. Daniel Stamer; Mark Johnson; Julian Solway; Jeffrey J. Fredberg; Ramaswamy Krishnan

doi:10.1039/C5IB00054H

High-throughput screening for modulators of cellular contractile force†

Chan Young Park,^a Enhua H. Zhou,^a Dhananjay Tambe,^a Bohao Chen,^b Tera Lavoie,^b Maria Dowell,^b Anton Simeonov,^c David J. Maloney,^c Aleksandar Marinkovic,^a Daniel J. Tschumperlin,^a Stephanie Burger,^a Matthew Frykenberg,^a James P. Butler,^a W. Daniel Stamer,^d Mark Johnson,^e Julian Solway,^b Jeffrey J. Fredberg^a and Ramaswamy Krishnan*^f

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* Corresponding authors

^a Molecular and Integrative Physiological Sciences, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA

^b Departments of Medicine, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA

^c National Center for Advancing Translational Sciences, National Institutes of Health, 6701 Democracy Boulevard, Bethesda, MD 20892, USA

^d Duke Eye Center, Duke University, 2351 Erwin Road, Durham, NC 27710, USA

^e Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA

^f Department of Emergency Medicine, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, Boston, MA 02215, USA
E-mail: rkrishn2@bidmc.harvard.edu

Abstract

When cellular contractile forces are central to pathophysiology, these forces comprise a logical target of therapy. Nevertheless, existing high-throughput screens are limited to upstream signalling intermediates with poorly defined relationships to such a physiological endpoint. Using cellular force as the target, here we report a new screening technology and demonstrate its applications using human airway smooth muscle cells in the context of asthma and Schlemm's canal endothelial cells in the context of glaucoma. This approach identified several drug candidates for both asthma and glaucoma. We attained rates of 1000 compounds per screening day, thus establishing a force-based cellular platform for high-throughput drug discovery.

This article is part of the themed collection: Mechanobiology

Integrative Biology

High-throughput screening for modulators of cellular contractile force†

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