Award Abstract # 1149401
CAREER: Biomechanical Phenotyping of Contractile Vascular Smooth Muscle Cells

NSF Org: CBET
Division of Chemical, Bioengineering, Environmental, and Transport Systems
Recipient: REGENTS OF THE UNIVERSITY OF MICHIGAN
Initial Amendment Date: May 11, 2012
Latest Amendment Date: May 11, 2012
Award Number: 1149401
Award Instrument: Standard Grant
Program Manager: Michele Grimm
CBET
 Division of Chemical, Bioengineering, Environmental, and Transport Systems
ENG
 Directorate for Engineering
Start Date: May 15, 2012
End Date: April 30, 2017 (Estimated)
Total Intended Award Amount: $449,115.00
Total Awarded Amount to Date: $449,115.00
Funds Obligated to Date: FY 2012 = $449,115.00
History of Investigator:
  • Jianping Fu (Principal Investigator)
    jpfu@umich.edu
Recipient Sponsored Research Office: Regents of the University of Michigan - Ann Arbor
1109 GEDDES AVE STE 3300
ANN ARBOR
MI  US  48109-1015
(734)763-6438
Sponsor Congressional District: 06
Primary Place of Performance: University of Michigan Ann Arbor
3003 S. State St.
Ann Arbor
MI  US  48109-1274
Primary Place of Performance
Congressional District:
06
Unique Entity Identifier (UEI): GNJ7BBP73WE9
Parent UEI:
NSF Program(s): Engineering of Biomed Systems
Primary Program Source: 01001213DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s): 004E, 017E, 1045
Program Element Code(s): 534500
Award Agency Code: 4900
Fund Agency Code: 4900
Assistance Listing Number(s): 47.041

ABSTRACT

CBET-1149401
Fu

The major goal of this CAREER proposal is to investigate mechanical force-mediated biomechanical responses of vascular smooth muscle cells, a key player in the context of mechanically exacerbated vascular diseases. Although there have been studies characterizing cellular responses of vascular smooth muscle cells to mechanical stimuli, the precise mechanical characteristics of their responses (including their innate contraction and cell stiffness modulation) remains largely elusive and uncharacterized. Given the critical involvements of contraction and mechanical stiffness modulations of vascular smooth muscle cells in regulating hypertension-induced vascular pathologies, our research is set out to specifically address this critical knowledge gap by leveraging our demonstrated expertise in microfabrication and cell mechanics to generate novel micromechanical tools to investigate force-mediated biomechanical phenotypic changes of vascular smooth muscle cells.

Biomechanical changes in vascular smooth muscle cell contraction and cell stiffness play an important functional role in regulating adaptation and remodeling of vessel walls in hypertension. Thus, a better understanding of the intimate interaction between external forces and changes in biomechanical properties of vascular smooth muscle cells will provide critical insights into how vascular smooth muscle cells transduce these forces and ultimately pave the way to developing drugs that specifically interfere with pressure-induced vascular pathologies. As an integral part of this CAREER proposal, a comprehensive education plan will be developed to target students from different educational levels and genders and ethnicities. Technologies developed in the context of this CAREER proposal will be used as vehicles for outreach activities targeting K-12 students in Ann Arbor and Ypsilanti school districts. We will develop educational modules aimed at altering preconceptions of science and engineering held by K-12 students. A new interdisciplinary course in Biomechanics will also be developed as an outcome of this CAREER proposal.

PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH

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(Showing: 1 - 10 of 31)
Ankur Singh, Shalu Suri, Ted T. Lee, Jamie M. Chilton, Marissa T. Cooke, Weiqiang Chen, Jianping Fu, Steven L. Stice, Hang Lu, Todd C. McDevitt, and Andrés J. García "Adhesive signature-based, label-free isolation of human pluripotent stem cells" Nature Methods , v.10 , 2013 , p.438
Christopher Moraes, Joseph M. Labuz, Yue Shao, Jianping Fu, and Shuichi Takayama "Supersoft lithography: Candy-derived soft microstructures to measure microtissue-generated stresses" Lab on Chip , v.15 , 2015 , p.3760 10.1039/C5LC00722D
David W. Dumbauld, Ted T. Lee, Ankur Singh, Jan Scrimgeour, Charles A. Gersbach, Evan A. Zamir, Jianping Fu, Christopher S. Chen, Jennifer E. Curtis, Susan W. Craig, and Andrés J. García "How vinculin regulates traction forces and adhesion strength" Proceedings of the National Academy of Sciences of the United States of America , v.110 , 2013 , p.9788
Dennis W. Zhou, Ted T. Lee, Shinuo Weng, Jianping Fu, and Andrés J. García "Effects of substrate stiffness and actomyosin contractility on coupling between force transmission and vinculin-paxillin recruitment at single focal adhesions" Molecular Biology of the Cell , 2017 10.1091/mbc.E17-02-0116
Di Chen, Yubing Sun, Cheri X. Deng, and Jianping Fu "Improving survival of disassociated human embryonic stem cells by mechanical stimulation using acoustic tweezing cytometry" Biophysical Journal , v.108 , 2015 , p.1315 10.1016/j.bpj.2015.01.033
Di Chen, Yubing Sun, Madhu S. R. Gudur, Yising Hsiao, Ziqi Wu, Jianping Fu, and Cheri X. Deng "Two bubble acoustic tweezing cytometry for biomechanical probing and stimulation of cells" Biophysical Journal , v.108 , 2015 , p.32 10.1016/j.bpj.2014.11.050
Kenichiro Taniguchi, Yue Shao, Ryan F. Townshend, Yu-Hwai Tsai, Cynthia J. DeLong, Shawn A. Lopez, Srimonta Gayen, Andrew M. Freddo, Deming J. Chue, Dennis J. Thomas, Jason R. Spence, Benjamin Margolis, Sundeep Kalantry, Jianping Fu, K. Sue O?Shea, and De "Lumen formation is an intrinsic property of isolated human pluripotent stem cells" Stem Cell Report , v.5 , 2015 , p.954 10.1016/j.stemcr.2015.10.015
Koh Meng Aw Yong, Yubing Sun, Sofia D. Merajver, and Jianping Fu "Mechanotransduction-induced reversible phenotypic switching in prostate cancer cells" Biophysical Journal , v.112 , 2017 , p.1236 DOI: 10.1016/j.bpj.2017.02.012
Mark T. Breckenridge, Ravi A. Desai, Michael T. Yang, Jianping Fu, and Christopher S. Chen "Substrates with engineered step changes in rigidity suggest a role for subcellular biases in traction force in driving durotaxis" Cellular and Molecular Bioengineering , v.7 , 2014 , p.26 10.1007/s12195-013-0307-6
Nhung Nguyen, Yue Shao, Alan Wineman, Jianping Fu, and Anthony Waas "Atomic force microscopy indentation and inverse analysis for non-linear viscoelastic identification of breast cancer cells" Mathematical Biosciences , v.277 , 2016 , p.77 10.1016/j.mbs.2016.03.015
Raymond Hiu-Wai Lam, Shinuo Weng, Wei Lu, and Jianping Fu "Live-cell subcellular measurement of cell stiffness using a microengineered stretchable micropost array membrane" Integrative Biology , v.4 , 2012 , p.1289-1298
(Showing: 1 - 10 of 31)

PROJECT OUTCOMES REPORT

Disclaimer

This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.

This research is to leverage recent advances in microfabrication to develop novel functional microscale tools for mechanistic investigation of force-mediated biomechanical responses of vascular smooth muscle cells (VSMCs), a key player in the context of mechanically exacerbated vascular diseases.  Although there have been studies characterizing the cellular responses of VSMCs to mechanical stimuli, the precise mechanical characteristics of their responses (including their innate contraction and cell stiffness modulation) remains largely elusive and uncharacterized.  Given the critical involvements of contraction and mechanical stiffness modulations of VSMCs in regulating hypertension-induced vascular pathologies, our research is set out to specifically address this critical knowledge gap by leveraging our demonstrated expertise in microfabrication and cell mechanics to generate a completely novel micromechanical platform to investigate force-mediated biomechanical phenotypic changes of VSMCs. 

Intellectual Merit Outcome: VSMCs are a key player for mechanically exacerbated vascular diseases.  A central goal of this project is thus to understand the early events involved in transducing extracellular forces into an intracellular signal and biological responses in VSMCs.  A critical enabling technology developed from this research is a unique micromechanical system, termed micropost array membrane (mPAM), in which some elastomeric microposts are integrated onto a stretchable membrane, such that when the base membrane is stretched, stretching forces can be transmitted through the posts to adherent cells seeded on top of the posts.  Using the mPAM, we have developed a novel strategy for whole-cell cell stiffness measurement with a subcellular spatial resolution.  We have further studied the functional role of actin cytoskeleton architecture in regulating cell shape-dependent mechano-sensitivity to directional cell stretch.  In our most recent effort, we have applied the mPAM system to perform live-cell subcellular studies of force-mediated cell adhesion dynamics, to examine the spatiotemporal evolution and coordination of adhesion dynamics and cytoskeleton contractile force.  Together, our research has developed novel technology platforms and methodologies for mechanobiology research.  Our mechanistic studies have also provided quantitative information about the mechanotransductive events centering on the cytoskeleton-cell adhesion-extracellular matrix signaling axis. 

Broader Impact Outcome: Owing to its multi-disciplinary nature, our research has seamlessly integrated knowledge from different fields including micro/nanoengineering, mechanobiology, live-cell imaging, and vascular biology.  To achieve our research, we have developed different integrated micromechanical tools that can be extremely useful for other researchers working in the general field of mechanobiology.  Our research has also established a novel mechanistic framework for understanding the mechanosensitive signaling mechanisms in vascular cells, which will be critically important for advancing mechanistic understanding of mechanically exacerbated vascular diseases.

            In this research, we have conducted educational activities to target students from different educational levels and genders and ethnicities.  Some of the technologies developed in our research have been used as vehicles for our outreach activities to K-12 students and other underrepresented female and minority students.  Through established educational programs at UM (including the UROP, SURE/SURE, and NNIN REU programs), we have recruited many undergrads to participate in our research.  Many of these undergraduate students are female and belong to minority groups.  By exposing the students to exciting challenges in research, these students become more motivated to pursue a career in science and engineering.  Lastly, we have developed a completely new interdisciplinary course in biomechanics for the College of Engineering at the University of Michigan.  This course can prepare engineer students to pursue research in a variety of multi-disciplinary areas such as tissue engineering and regenerative medicine that are of great importance to our society today.  

 


Last Modified: 05/10/2017
Modified by: Jianping Fu

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