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Overview

Normal morphogenesis and physiology require that cellular signaling, gene expression and behavior be closely coordinated with tissue architecture and mechanical forces. Thus, the type and physical properties of the extracellular matrix, and the mechanical forces to which cells are exposed govern cell structure, gene expression and behavior. Nowhere is this more evident than in the cardiovascular system, where forces from blood flow (blood pressure and fluid shear stress, the frictional forces that flowing blood exerts on vessel walls) sculpt the developing heart and vasculature, and govern their remodeling throughout life. Conversely, the major diseases that afflict humankind, including atherosclerosis, heart failure and cancer, are due in essence to breakdowns in these processes.

The Schwartz lab combines basic cell biological studies of the fundamental basis for integrin signaling, signal integration and mechanotransduction with disease models, to elucidate the mechanistic basis of both normal physiology and disease. Our approaches integrate biophysical tools, high resolution imaging, protein engineering, cell culture and cell biological assays, with animal models of disease and analysis of human specimens. The goal of these studies is to deeply understand molecular and biophysical mechanisms, and to test and apply this knowledge to relevant biological systems, in particular to understanding and curing vascular diseases.

  

Fundamentals of Flow Sensing

Fluid shear stress is a very weak force, typically about 1/100th of the usual traction forces that endothelial cells exert on their extracellular matrix, yet it has very strong effects on vascular development, remodeling and function. Endothelial cells are specialized to sense and respond to these forces but the fundamental mechanisms of mechanotransduction are poorly understood. Our newest data shows that while the junctional mechanosensory complex is a true mechanotransducers, it is never the less downstream of other events [1]. This system therefore provides a starting point for elucidating the upstream pathway. We are currently doing siRNA and CRISPR-Cas9 based whole genome screening to identify all of the components involved in flow sensing. With the use of our other tools, such as in vitro assays and the molecular tensions sensor [2], we are working to delineate the complete upstream pathways by which cells sense fluid shear stress.
  1. Conway, D.E., et al., Fluid shear stress on endothelial cells modulates mechanical tension across VE-cadherin and PECAM-1. Curr Biol, 2013. 23(11): p. 1024-30.
  2. Grashoff, C., et al., Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Nature, 2010. 466(7303): p. 263-6.