The overall goal of this Program Project is to understand in detail how integrin-mediated adhesions mature and how this process determines signaling outputs. Adhesion maturation is highly dependent on physical forces, whether from endogenous myosin or applied externally through the extracellular matrix. Thus, comparison of normal adhesion ultrastructure and dynamics with responses to applied force will elucidate mechanisms of mechanotransduction. This Program Project will develop a model for mechanotransduction at matrix adhesions that integrates adhesion ultrastructure, biochemical interactions, temporal and spatial dynamics of multiprotein assemblies and signaling networks. We will analyze mechanotransduction in the context of cell migration as an important physiological output of adhesion mechanics and signaling. To achieve this, we have formed a unique team of long-standing collaborators who will implement a multifaceted experimental approach that includes molecular cell biology, biochemistry, biophysical approaches, material science, computational and mathematical analysis, and correlated high-resolution light and electron microscopy.

Public Health Relevance

Matrix adhesions sense their mechanical environment and thereby modulate signals that regulate proliferation, differentiation, migration, and cell death. Shifts in force, therefore, can produce developmental defects and contribute to vascular and chronic inflammatory diseases, tumor formation and metastasis. Despite its importance, the mechanism underlying the transduction of force to biological signal is not understood. Our multifaceted approach will reveal its mechanistic and structural basis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM098412-03
Application #
8550088
Study Section
Special Emphasis Panel (ZRG1-CB-D (40))
Program Officer
Deatherage, James F
Project Start
2011-09-30
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$1,468,099
Indirect Cost
$243,934
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

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