Understanding how various biomolecules embedded within biochemical and mechanical networks are coordinated over multiple length and time scales to produce orchestrated cell behaviors requires characterization of their biochemical and biophysical properties in their native cellular context. However this represents a major challenge and our current understanding of the native behaviors of biomolecules has been limited by the lack of suitable techniques to measure and manipulate their dynamic properties in living cells. For example, to reveal causal connections and achieve a systems understanding of the signal transduction networks in living cells, a large set of molecular tools, designed to specifically perturb signaling pathways in situ and to quantitatively measure the cellular response, must be developed. Furthermore, very little is known about the mechanical properties and behaviors of molecules involved in force generation, cellular mechanics maintenance and mechanotransduction in a living cell due, in large part, to the lack of experimental methodologies for intracellular measurement and manipulation of biophysical properties. I propose to develop such molecular tools as genetically encodable magnetic probes by integrating molecular engineering strategies, chemical and cell biological approaches, and state-of-the-art biophysical measurement and manipulation combining single-molecule imaging and magnetic tweezers. This work will identify new strategies for simultaneous measurement and manipulation of intracellular molecular events and will provide enabling technologies for probing biochemical and biophysical processes in living cells. A better understanding of life processes at the molecular level will lead to new insights in treating diseases that result from dysregulation of these processes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZGM1-NDPA-B (02))
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Knowlton, John R
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Johns Hopkins University
Schools of Medicine
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Sample, Vedangi; Mehta, Sohum; Zhang, Jin (2014) Genetically encoded molecular probes to visualize and perturb signaling dynamics in living biological systems. J Cell Sci 127:1151-60
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Hertel, Fabian; Zhang, Jin (2013) Monitoring of post-translational modification dynamics with genetically encoded fluorescent reporters. Biopolymers :
Sample, Vedangi; Ni, Qiang; Mehta, Sohum et al. (2013) Controlling enzymatic action in living cells with a kinase-inducible bimolecular switch. ACS Chem Biol 8:116-21
Depry, Charlene; Mehta, Sohum; Zhang, Jin (2013) Multiplexed visualization of dynamic signaling networks using genetically encoded fluorescent protein-based biosensors. Pflugers Arch 465:373-81