In this Program Project Grant our overarching hypothesis is that alterations in the assembly states and mechanical properties of cytoskeletal IF, specifically the type III IF composed of vimentin (VIF), play important roles in regulating the micromechanical properties of cells in response to mechano- and chemosignalling. These studies are critically important as IF are major elements of the cytoskeletal system of mammalian cells and yet their specific functions in cell motility remain unknown. The 6 Project Leaders, and their research aims are as follows: R. Goldman, Northwestern University, will determine how the vimentin IF (VIF) system changes in response to mechanical and chemical signals, and will purify and characterize the vimentin precursors that form as VIF assemble and disassemble. V. Gelfand, Northwestern University will determine the relationship between VIF with microtubules and actin filaments, identify the molecular motors responsible for translocating VIF precursors, and investigate how VIF affect cytoskeletal dynamics and microtubule (MT) dynamics. G. Danuser, Harvard University, will test the hypotheses that VIF network formation involves a spatially distributed assembly line, that this process involves molecular motors, and that VIF network assembly modulates assembly of MT and microfilaments (MF). D. Weitz, Harvard University, will determine the micromechanical properties of in vitro asembled VIF networks prepared from purified vimentin, native VIF networks isolated from cells and in living cells. P. Janmey, University of Pennsylvannia, will determine how the VIF network contributes to the micromechanical properties of living cells and how this changes in response to substrate stiffness and external forces. P. Burkhard, University of Connecticut, will use biophysical techniques and X-ray crystallography to determine the structure and biophysical properties of the vimentin dimer and study the formation of VIF assembly intermediates. In all of these studies, the regulatory function of different posttranslational phosphorylation events will be examined.

Public Health Relevance

Intermediate Filaments (IF) are structural proteins involved in determining cell shape, movement and mechanical integrity. However, their specific functions remain unknown. We propose studies aimed at understanding their specific functions in the movement and mechanical properties of cells. These basic studies will provide insights into their normal functions and will help explain their defective functions in the many diseases attributed to mutations in the genes encoding the different IF proteins.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CB-D)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
United States
Zip Code
Chernoivanenko, Ivan S; Matveeva, Elena A; Gelfand, Vladimir I et al. (2015) Mitochondrial membrane potential is regulated by vimentin intermediate filaments. FASEB J 29:820-7
Mendez, M G; Restle, D; Janmey, P A (2014) Vimentin enhances cell elastic behavior and protects against compressive stress. Biophys J 107:314-23
Chopra, Anant; Murray, Maria E; Byfield, Fitzroy J et al. (2014) Augmentation of integrin-mediated mechanotransduction by hyaluronic acid. Biomaterials 35:71-82
Guo, Ming; Ehrlicher, Allen J; Jensen, Mikkel H et al. (2014) Probing the stochastic, motor-driven properties of the cytoplasm using force spectrum microscopy. Cell 158:822-32
Schmid, Lothar; Weitz, David A; Franke, Thomas (2014) Sorting drops and cells with acoustics: acoustic microfluidic fluorescence-activated cell sorter. Lab Chip 14:3710-8
Wang, Yu-Hsiu; Slochower, David R; Janmey, Paul A (2014) Counterion-mediated cluster formation by polyphosphoinositides. Chem Phys Lipids 182:38-51
Shabbir, Shagufta H; Cleland, Megan M; Goldman, Robert D et al. (2014) Geometric control of vimentin intermediate filaments. Biomaterials 35:1359-66
Murray, Maria E; Mendez, Melissa G; Janmey, Paul A (2014) Substrate stiffness regulates solubility of cellular vimentin. Mol Biol Cell 25:87-94
Kapus, Andras; Janmey, Paul (2013) Plasma membrane--cortical cytoskeleton interactions: a cell biology approach with biophysical considerations. Compr Physiol 3:1231-81
Abate, Adam R; Hung, Tony; Sperling, Ralph A et al. (2013) DNA sequence analysis with droplet-based microfluidics. Lab Chip 13:4864-9

Showing the most recent 10 out of 16 publications