The joint interest of Danuser and Horwitz is to identify mechanisms by which mechanical forces and chemical signals integrate to regulate cell migration. One central question in our labs is how cell external and cell internal forces at integrin-mediated cell matrix adhesions change composition, structure and signaling properties of adhesion sites. The key challenge in addressing this question is the nested feedback interaction between force production, adhesion strengthening (also referred to as adhesion reinforcement), and adhesion signaling (Fig 1). In this scenario, conventional perturbation experiments, where one component is changed and resulting phenotype is interpreted in the context of the intervention, provide limited information about the interdependence of the processes. Therefore, our labs will implement a strategy that requires minimal perturbation. We will use live-cell imaging approaches to simultaneously measure the basal activities of multiple processes and apply statistical signal processing to derive from this data the hierarchy and kinetics of the relations between activities. Predictions from this non-perturbing approach will then be tested by acute mechanical simulation and tracking of molecular activities that lead to adhesion strengthening and signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM098412-04
Application #
8728275
Study Section
Special Emphasis Panel (ZRG1-CB-D)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
$386,714
Indirect Cost
$48,212
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kumar, Abhishek; Ouyang, Mingxing; Van den Dries, Koen et al. (2016) Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity. J Cell Biol 213:371-83
Vertelov, Grigory; Gutierrez, Edgar; Lee, Sin-Ae et al. (2016) Rigidity of silicone substrates controls cell spreading and stem cell differentiation. Sci Rep 6:33411
Xu, Xiao-Ping; Kim, Eldar; Swift, Mark et al. (2016) Three-Dimensional Structures of Full-Length, Membrane-Embedded Human α(IIb)β(3) Integrin Complexes. Biophys J 110:798-809
Brenner, Michael D; Zhou, Ruobo; Conway, Daniel E et al. (2016) Spider Silk Peptide Is a Compact, Linear Nanospring Ideal for Intracellular Tension Sensing. Nano Lett 16:2096-102
Hassler, Justin R; Scheuner, Donalyn L; Wang, Shiyu et al. (2015) The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells. PLoS Biol 13:e1002277
Bober, Brian G; Gutierrez, Edgar; Plaxe, Steven et al. (2015) Combinatorial influences of paclitaxel and strain on axonal transport. Exp Neurol 271:358-67
Lagarrigue, Frederic; Vikas Anekal, Praju; Lee, Ho-Sup et al. (2015) A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration. Nat Commun 6:8492
Han, Sangyoon J; Oak, Youbean; Groisman, Alex et al. (2015) Traction microscopy to identify force modulation in subresolution adhesions. Nat Methods 12:653-6
Page, Christopher; Hanein, Dorit; Volkmann, Niels (2015) Accurate membrane tracing in three-dimensional reconstructions from electron cryotomography data. Ultramicroscopy 155:20-6
Lee, Kwonmoo; Elliott, Hunter L; Oak, Youbean et al. (2015) Functional hierarchy of redundant actin assembly factors revealed by fine-grained registration of intrinsic image fluctuations. Cell Syst 1:37-50

Showing the most recent 10 out of 24 publications