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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072744-09
Application #
8313992
Study Section
Special Emphasis Panel (ZRG1-CB-N (02))
Program Officer
Nie, Zhongzhen
Project Start
2004-12-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$368,026
Indirect Cost
$130,426
Name
University of Illinois Urbana-Champaign
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Wang, Ning (2014) Stem cells go soft: pliant substrate surfaces enhance motor neuron differentiation. Cell Stem Cell 14:701-3
Tan, Youhua; Tajik, Arash; Chen, Junwei et al. (2014) Matrix softness regulates plasticity of tumour-repopulating cells via H3K9 demethylation and Sox2 expression. Nat Commun 5:4619
Poh, Yeh-Chuin; Chen, Junwei; Hong, Ying et al. (2014) Generation of organized germ layers from a single mouse embryonic stem cell. Nat Commun 5:4000
Seong, Jihye; Wang, Ning; Wang, Yingxiao (2013) Mechanotransduction at focal adhesions: from physiology to cancer development. J Cell Mol Med 17:597-604
Uda, Yuhei; Poh, Yeh-Chuin; Chowdhury, Farhan et al. (2011) Force via integrins but not E-cadherin decreases Oct3/4 expression in embryonic stem cells. Biochem Biophys Res Commun 415:396-400
Kasza, Karen E; Vader, David; Koster, Sarah et al. (2011) Imaging techniques for measuring the materials properties of cells. Cold Spring Harb Protoc 2011:pdb.top107
Li, Dong; Zhou, Jiaxi; Chowdhury, Farhan et al. (2011) Role of mechanical factors in fate decisions of stem cells. Regen Med 6:229-40
Yum, Kyungsuk; Yu, Min-Feng; Wang, Ning et al. (2011) Biofunctionalized nanoneedles for the direct and site-selective delivery of probes into living cells. Biochim Biophys Acta 1810:330-8
Leckband, Deborah E; le Duc, Quint; Wang, Ning et al. (2011) Mechanotransduction at cadherin-mediated adhesions. Curr Opin Cell Biol 23:523-30
Kasza, Karen E; Vader, David; Koster, Sarah et al. (2011) Magnetic twisting cytometry. Cold Spring Harb Protoc 2011:pdb.prot5599

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