Human Stress Response Specificity Through Biochemical Resonance Selectivity

When a cell experiences a variety of environmental stresses the genetic responses in all eukaryotic cells are accomplished by the mitogen activated protein kinase cascade, a multilayered network of enzymes. However, specific mechanisms for selecting and activating responses appropriate to received stresses have remained elusive. The PI's lab has discovered a novel mechanism for biochemical enzyme specificity and eukaryotic gene regulation by the master stress response regulator protein called p38 MAPK. It was found that p38 MAPK encodes information regarding experienced stresses as different frequency oscillations of its activation state, and these oscillations are used to select specific responses through frequency-dependent resonance of oscillating biochemical reactions between p38 and downstream targets. This phenomenon is called bioresonance, which provides a mechanism where a single enzyme can be used to specifically control a broad range of targets without requiring alterations to its sequence or shape simply by altering the frequency with which its activation state oscillates. In this proposal the PI will explore the generality and applicability of bioresonance to the other MAPK master regulator proteins, potentially opening entirely new approaches for controlling eukaryotic and human gene expression. This work has profound implications for pharmaceutical development. The PI's results already demonstrate that specific human genetic responses can be triggered independently of the precise chemical or physical nature of the stimulus. This work has the potential to make a major contribution to making inexpensive and effective therapeutic approaches available to larger portions of society. By testing the hypothesis that bioresonance is a widespread control scheme within the human MAPK signaling network, we can thoroughly explore the applicability of bioresonance to MAPK signaling. This research will provide new insight into how human cells coordinate genetic responses to stimuli and to understanding the principles driving connectivity of and signal transduction through the MAPK network. The PI will apply the techniques that were have developed to study p38 bioresonance to the other MAPK master regulator proteins, where similar oscillations have previously been observed of much higher frequency than those we have measured in p38. The PI will develop Förster resonance energy transfer (FRET) based reporters for the activation state of ERK1/2, ERK5, and JNK, as well as their protein transcription factor substrates. Once validated, these reporters will allow us to quantitatively describe interactions within all modules of the MAPK network at the single cell level and in real time, providing unparalleled insight into how information flows from the external environment to the genome to effect changes in gene expression. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2609970 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Thomas Kuhlman | Institution: University of California-Riverside, RIVERSIDE, CA | Award Amount: $400,000 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2609970 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2609970.html