Bioengineering approaches to map mechanotransduction in the living cell Abstract Mechanical forces strongly influence the growth and form of virtually every tissue and organ in our bodies. Yet little is known about the mechanism by which individual cells sense these mechanical signals and transduce them into changes in intracellular biochemistry and gene expression - a process known as mechanotransduction. We find that, surprisingly, a local surface stress is concentrated in the cytoplasm and propagated rapidly along the cytoskeleton to distant sites to activate specific enzymes, representing drastic departures from existing prevailing models of mechanotransduction. In this revised renewal application we propose three aims.
Aim 1 is to dissect the molecular differences between growth factor induced and stress-induced Src and Rac activation.
Aim 2 is to test the hypothesis that physical interactions of nuclear proteins coilin-SMN can be directly altered by a local stress at the cell surface.
Aim 3 is to elucidate mechanisms of mechanical signaling mediated spreading and differentiation in embryonic stem cells. The proposed bioengineering research combines mechanical quantification of the living cell with biochemical and biological measurements. The experimental approach is to measure with high spatial and temporal resolution the cytoplasmic and subnuclear structural deformation and simultaneously quantify biochemical activities, protein dynamics, and gene expressions in a living cell. The current project may have implications in elucidating specific loci and protein complexes of mechanotransduction at sites deep in the cytoplasm and the nucleus that are responsible for regulation of gene expression and differentiation. A growing body of evidence demonstrates that abnormal mechanical forces may contribute to the development of various diseases, such as atherosclerosis, asthma, progeria, and cancer progression, by altering form and function of living cells. The present study may provide a unique way to identify potential structural and molecular targets of mechanotransduction for therapeutic intervention in the future.
A growing body of evidence demonstrates that abnormal mechanical forces may contribute to the development of various diseases, such as atherosclerosis, asthma, progeria, and cancer progression, by altering form and function of living cells. The present study may provide a unique way to identify potential structural and molecular targets of mechanotransduction for therapeutic intervention in the future.
|Chowdhury, Farhan; Do?anay, Sultan; Leslie, Benjamin J et al. (2018) Cdc42-dependent modulation of rigidity sensing and cell spreading in tumor repopulating cells. Biochem Biophys Res Commun 500:557-563|
|Zhang, Yuejin; Wei, Fuxiang; Poh, Yeh-Chuin et al. (2017) Interfacing 3D magnetic twisting cytometry with confocal fluorescence microscopy to image force responses in living cells. Nat Protoc 12:1437-1450|
|Wang, Ning (2017) Review of Cellular Mechanotransduction. J Phys D Appl Phys 50:|
|Tan, Youhua; Wood, Adam Richard; Jia, Qiong et al. (2017) Soft matrices downregulate FAK activity to promote growth of tumor-repopulating cells. Biochem Biophys Res Commun 483:456-462|
|Ma, Jingwei; Zhang, Yi; Tang, Ke et al. (2016) Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles. Cell Res 26:713-27|
|Jia, Q; Zhou, W; Yao, W et al. (2016) Downregulation of YAP-dependent Nupr1 promotes tumor-repopulating cell growth in soft matrices. Oncogenesis 5:e220|
|Muhamed, Ismaeel; Wu, Jun; Sehgal, Poonam et al. (2016) E-cadherin-mediated force transduction signals regulate global cell mechanics. J Cell Sci 129:1843-54|
|Tajik, Arash; Zhang, Yuejin; Wei, Fuxiang et al. (2016) Transcription upregulation via force-induced direct stretching of chromatin. Nat Mater 15:1287-1296|
|Chen, Junjian; Zhou, Wenwen; Jia, Qiong et al. (2016) Efficient extravasation of tumor-repopulating cells depends on cell deformability. Sci Rep 6:19304|
|Li, Yong; Luo, Shunqun; Ma, Ruihua et al. (2015) Upregulation of cytosolic phosphoenolpyruvate carboxykinase is a critical metabolic event in melanoma cells that repopulate tumors. Cancer Res 75:1191-6|
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