Cell type-specific molecular mechanisms by which glucose availability regulates cell mechanics and function

The proposed study aims to address the following three critical questions in cell mechanobiology field for betterunderstanding of how cells translate external biochemical cues to regulate their function via modulation of cellmechanics. (1) What are the molecular mechanisms by which extracellular glucose levels alter cell mechanicsand functions? Glucose is an essential nutrient for virtually all types of cells including immune cells and epithelialcells to support their survival and proper function. Glucose level varies in local tissues due to differentialconsumption rate by cells and/or altered interstitial fluid pressure in pathological conditions such as inflammationand cancer. Dynamic rearrangement of actin cytoskeleton is critical for cell physiology. Cells spend 50% of theirenergy to support actin cytoskeleton rearrangement which determines cell mechanics and function. Cellmechanotypes include cell shape deformability and contractility. We have reported that extracellular glucoselevel alters cell mechanics and we will further elucidate the underlying molecular mechanisms by which glucosemetabolism regulates cell mechanotype changes. (2) How cell mechanics is regulated in spatiotemporalframework? Cell mechanotype alterations span many length scales and timescales. It is intuitive that cellmechanotype changes can happen promptly after triggered by external cues as cytoskeleton remodeling andpost-translational modification of myosin activating signaling pathway can happen within seconds to minutes.However we don't understand how dynamically cell mechanotype changes are regulated over time in subcellularresolution. We are in a unique position to investigate the persistency reversibility oscillation and memorizationof altered cell mechanotypes. (3) Are there shared signaling axes or cell type-specific axis to regulate cellmechanics in different cell types? Our published and preliminary data shows that glucose-induced changes incell mechanics and function are cell type-dependent. M1 is similar to MCF10A cells while M0 and M2 aresimilar to MDA-MB-231 cells in terms of their mechanotype changes in response to extracellular glucose level:no significant changes were observed from M1 and MCF10A while increased stiffness and contractility wereobserved from M0 M2 and MDA-MB-231 cells with high glucose levels. We will investigate the shared ordistinct molecular mechanisms by which cell mechanics are regulated. Successful completion of the proposedwork will significantly improve our understanding on the effects of extracellular glucose levels on cell mechanicsand function. Furthermore this novel knowledge will serve as a basis of future translational studies utilizing thecell mechanotypes for effective therapeutic options on various diseases including cancer and infectious diseases.