Integrin-mediated cell adhesion to extracellular matrices regulates the organization, maintenance and repair of numerous tissues, and abnormalities in adhesive interactions are often associated with pathological states. The adhesive process comprises integrin receptor binding to their extracellular ligand, integrin clustering, and assembly of discrete supramolecular structures containing cytoskeletal and signaling molecules. These focal adhesion complexes function as structural links and signal transduction elements between the cell and its extracellular environment. While significant progress has been attained in deciphering biochemical pathways regulating adhesion, the mechanical interactions between a cell and its environment remain poorly understood. The objective of this renewal application is to analyze the role of nanoscale organization and structure of focal adhesions in the generation of cell-extracellular matrix forces. Our central hypothesis is that the precise nanoscale organization of integrins and their interaction with specific cytoskeletal elements regulate adhesive interactions by controlling the distribution of mechanical forces within the adhesive interface. The rationale for this project is that it will provide new insights into how the structure of focal adhesion complexes regulates adhesive processes, such as adhesion strength and migration.
Aim 1 : Analyze the effects of nanoscale focal adhesion structure (cluster size, spacing) on cell adhesive force and migration.
Aim 2 : Elucidate the contributions of integrin-cytoskeleton interactions at the adhesion complex to adhesion strength and migration. The proposed research is innovative because it integrates robust quantitative assays, nanopatterning approaches, and unique cell biology reagents to precisely manipulate focal complex architecture and biomolecular interactions in order to analyze how these adhesive complexes generate adhesive forces. We will elucidate the contributions of nanoscale clustering to adhesive force generation. These rigorous analyses will yield new, sensitive measurements of the contributions of biomolecular interactions between focal complex components to adhesive force. Collectively, this research will generate a new understanding of the regulation of mechanical interactions between a cell and its extracellular matrix.

Public Health Relevance

The generation of adhesive forces is essential to cellular functions in physiological processes and pathological conditions. The objective of this research is to derive a fundamental understanding of the molecular events at the adhesive interface that regulate cell adhesive forces. This work will provide new insights in the molecular mechanisms controlling adhesive processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065918-08
Application #
7858140
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Flicker, Paula F
Project Start
2002-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
8
Fiscal Year
2010
Total Cost
$278,065
Indirect Cost
Name
Georgia Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30332
Zhou, Dennis W; Lee, Ted T; Weng, Shinuo et al. (2017) Effects of substrate stiffness and actomyosin contractility on coupling between force transmission and vinculin-paxillin recruitment at single focal adhesions. Mol Biol Cell 28:1901-1911
Miroshnikova, Y A; Rozenberg, G I; Cassereau, L et al. (2017) ?5?1-Integrin promotes tension-dependent mammary epithelial cell invasion by engaging the fibronectin synergy site. Mol Biol Cell 28:2958-2977
Cermeño, Efraín A; García, Andrés J (2016) Tumor-Initiating Cells: Emerging Biophysical Methods of Isolation. Curr Stem Cell Rep 2:21-32
Elloumi-Hannachi, Imen; García, José R; Shekeran, Asha et al. (2015) Contributions of the integrin ?1 tail to cell adhesive forces. Exp Cell Res 332:212-22
Fernandez, Isabel; Martin-Garrido, Abel; Zhou, Dennis W et al. (2015) Hic-5 Mediates TGF?-Induced Adhesion in Vascular Smooth Muscle Cells by a Nox4-Dependent Mechanism. Arterioscler Thromb Vasc Biol 35:1198-206
Zhou, Dennis W; García, Andrés J (2015) Measurement systems for cell adhesive forces. J Biomech Eng 137:020908
Jannie, Karry M; Ellerbroek, Shawn M; Zhou, Dennis W et al. (2015) Vinculin-dependent actin bundling regulates cell migration and traction forces. Biochem J 465:383-93
García, José R; Singh, Ankur; García, Andrés J (2014) High fidelity nanopatterning of proteins onto well-defined surfaces through subtractive contact printing. Methods Cell Biol 119:277-92
Dumbauld, David W; García, Andrés J (2014) A helping hand: How vinculin contributes to cell-matrix and cell-cell force transfer. Cell Adh Migr 8:550-7
Seong, Jihye; Tajik, Arash; Sun, Jie et al. (2013) Distinct biophysical mechanisms of focal adhesion kinase mechanoactivation by different extracellular matrix proteins. Proc Natl Acad Sci U S A 110:19372-7

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