The key end-effector of acute airway narrowing in asthma is contraction of the airway smooth muscle (ASM) cell. The key motor protein that drives ASM contraction is myosin. Both the myosin-based contractile apparatus and its cytoskeletal (CSK) scaffolding are dynamic structures that are in a continuous state of remodeling, but their dynamics are not well defined. This competing renewal BRP application describes an interdisciplinary design-directed bioengineering project to fill that gap of knowledge. We propose to develop micromechanical technologies to measure cytoskeletal rheology, contractility, and remodeling. These technologies are based upon forced nano-scale motions of microbeads tightly bound to the cytoskeleton of the airway smooth muscle cell, spontaneous nano-scale motions of those same beads, and the relationship between them. Taken together, these technologies comprise a suite of novel tools that is unequalled in its ability to characterize cytoskeletal mechanics at cellular and subcellular levels. From the point of view of clinical sciences, they have bearing upon the ASM cell and the role of that cell in bronchospasm, which is our stated goal. But these technologies will have bearing as well upon any integrative (patho)physiological process that has prominent mechanical components, including vasospasm, embryonic development, pattern formation, wound healing, crawling, metastasis, invasion, and mechanotransduction. The Scientific Steering group is comprised of: Jeffrey J. Fredberg, Principal Investigator; Ben Fabry, Lead Investigator, U. Erlangen, addressing signal processing and algorithm development; Geoffrey Maksym, Lead Investigator, U. Dalhousie, addressing imaging systems and CSK remodeling; Daniel Navajas, Lead Investigator, U. Barcelona, addressing cell stretch.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL065960-06
Application #
6943705
Study Section
Special Emphasis Panel (ZRG1-RES-D (50))
Program Officer
Croxton, Thomas
Project Start
2000-09-30
Project End
2010-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
6
Fiscal Year
2005
Total Cost
$709,046
Indirect Cost
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Richter, S; Gerum, R; Winterl, A et al. (2018) Phase transitions in huddling emperor penguins. J Phys D Appl Phys 51:
Gerum, Richard; Richter, Sebastian; Fabry, Ben et al. (2018) Structural organisation and dynamics in king penguin colonies. J Phys D Appl Phys 51:
Steinwachs, Julian; Metzner, Claus; Skodzek, Kai et al. (2016) Three-dimensional force microscopy of cells in biopolymer networks. Nat Methods 13:171-6
Auernheimer, Vera; Lautscham, Lena A; Leidenberger, Maria et al. (2015) Vinculin phosphorylation at residues Y100 and Y1065 is required for cellular force transmission. J Cell Sci 128:3435-43
Lautscham, Lena A; Lin, Corey Y; Auernheimer, Vera et al. (2014) Biomembrane-mimicking lipid bilayer system as a mechanically tunable cell substrate. Biomaterials 35:3198-207
Lange, Janina R; Fabry, Ben (2013) Cell and tissue mechanics in cell migration. Exp Cell Res 319:2418-23
Steward Jr, Robert L; Rosner, Sonia R; Zhou, Enhua H et al. (2013) Illuminating human health through cell mechanics. Swiss Med Wkly 143:w13766
Zhou, Enhua H; Martinez, Fernando D; Fredberg, Jeffrey J (2013) Cell rheology: mush rather than machine. Nat Mater 12:184-5
Coughlin, Mark F; Bielenberg, Diane R; Lenormand, Guillaume et al. (2013) Cytoskeletal stiffness, friction, and fluidity of cancer cell lines with different metastatic potential. Clin Exp Metastasis 30:237-50
Mizrahi, Natalya; Zhou, Enhua H; Lenormand, Guillaume et al. (2012) Low intensity ultrasound perturbs cytoskeleton dynamics. Soft Matter 8:2438-2443

Showing the most recent 10 out of 56 publications