BRITE Pivot: Identification of the Biophysical Mechanisms Regulating Nuclear-Cytosolic Transport Capacity

Ohio State University, The, Columbus OH

Investigators

Abstract

The overall goal of this Boosting Research Ideas for Transformative and Equitable Advances in Engineering (BRITE) Pivot research project is to develop a comprehensive understanding of the biophysical regulation of the movement of large molecules in and out of the cell nucleus. The nucleus is the largest structure in a cell and has two membranes surrounding the DNA. The double membrane has thousands of small pores called nuclear pore complexes (NPCs). The NPCs are how molecules (including proteins and mRNA) move into and out of the nucleus. This movement of molecules through NPCs is so important that mammals (humans) and single-cell organisms all have it. Problems with NPC transport occurs in many diseases, including cancer, infection by viruses, cardiovascular disease, and aging. Because nearly every cell has a nucleus, the new methods for measuring the molecules moving through the NPCs will be useful for research in cell biology, biophysics, and mechanobiology. The educational goal of this project is to introduce undergraduate students to the growing field of nucleus mechanobiology by using these new research findings in educational and outreach experiences. The macromolecular structure of individual nuclear pore complexes (NPCs) has been characterized in great detail, including the localization and dynamics of many nucleoporin proteins. However, the dynamics and regulation of NPC nuclear transport, at a spatial and temporal level, have yet to be carefully studied, in part due to a limitation in tools for detection of these processes. In this project biosensor-based approaches will be developed and applied to better understand NPC nuclear transport in order to understand of the biochemical and biomechanical factors that regulate NPC transport. Results from these studies will provide substantial insight into yet-unanswered fundamental questions concerning NPC regulation of transport: 1) are there are spatial differences in NPC transport activity? 2) are individual NPCs specialized for import versus export? and 3) does mechanical loading of NPCs alter nuclear-cytosolic transport? This transformative research will provide a new understanding of the biophysical regulation of NPC nuclear-cytosolic transport. 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.