Defining Mechanical Landscapes at Cell-Cell Junctions

University Of Massachusetts Amherst, Amherst MA

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Abstract

PROJECT SUMMARY/ABSTRACT The long-term goal of my research group is to develop “next-generation” nucleic acid-based platform for understanding how living organisms function and for disease diagnostics. In particular, we are creating a series of DNA probes for measuring cell membrane biophysical interactions, especially the biomechanical features at cell-cell junctions, as well as developing fluorogenic RNA aptamer-based sensors for targeted imaging inside living organisms. Our immediate goal for the next five years is to make precise intercellular force measurement and regulation readily available for implementation in life science laboratories. We will demonstrate how these novel DNA-based tools can be broadly used to understand the basic mechanical principles of development, physiology, and disease. These DNA mechanical probes and actuators will also serve as the critical foundation for developing novel strategies in tissue engineering, regenerative medicine, and cell therapy. Mechanical forces play fundamental roles in many intrinsic and collective cellular processes, such as tissue regeneration, morphogenesis, and tumor metastasis. While extensive studies have focused on the forces between cells and extracellular matrices, mechanical interactions among individual cells appear to be important yet poorly characterized. These intercellular forces are known to be critical during wound healing, cancer cell invasion, and other developmental and homeostatic processes. However, the molecular principles that govern these finely balanced mechanotransduction events are still poorly understood. To depict the mechanisms of these collective cellular processes, it is essential to measure and fine-tune intercellular forces at the molecular level, and then correlate the patterns of mechanical landscapes with the specific molecular machineries that regulate cellular signaling. In the past project period, we have developed precise and easy-to-use DNA-based fluorescent probes to visualize and quantify forces at cell-cell junctions. These synthetic DNA probes can spontaneously anchor onto the external surfaces of live cell membranes and allow sensitive imaging of a broad range of intercellular molecular forces simply after a brief incubation. During the next 5-year project period, we plan to further develop highly robust, versatile, and high-throughput DNA-based mechanoprobes and novel mechanical actuators. These tools will be further used to provide unique insights for elucidating the mechanical mechanisms of several key collective mechanosensitive cellular events in neural development, cancer metastasis, and immunology. High-throughput screening platforms will also be validated and applied for the identification of novel modulators of intercellular forces and potential drug candidates. In contrast to many current mechanobiology studies that are based on techniques typically performed in only a few specialized laboratories, the DNA probes, actuators, and screening platforms developed in this project can be potentially widely adopted for measuring and regulating molecular forces at cell-cell junctions.