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.
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.
|Wu, Pei-Hsun; Aroush, Dikla Raz-Ben; Asnacios, Atef et al. (2018) A comparison of methods to assess cell mechanical properties. Nat Methods 15:491-498|
|Robert, Amélie; Tian, Peirun; Adam, Stephen A et al. (2018) Kinesin-dependent transport of keratin filaments: a unified mechanism for intermediate filament transport. FASEB J :fj201800604R|
|Li, Wen; Zhang, Liyuan; Ge, Xuehui et al. (2018) Microfluidic fabrication of microparticles for biomedical applications. Chem Soc Rev 47:5646-5683|
|Wang, Zheng; Divanyan, Alex; Jourd'heuil, Frances L et al. (2018) Vimentin expression is required for the development of EMT-related renal fibrosis following unilateral ureteral obstruction in mice. Am J Physiol Renal Physiol 315:F769-F780|
|Wang, Liqun; Xia, Jing; Li, Jonathan et al. (2018) Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease. Nat Commun 9:1899|
|Bucki, Robert; Durna?, Bonita; W?tek, Marzena et al. (2018) Targeting polyelectrolyte networks in purulent body fluids to modulate bactericidal properties of some antibiotics. Infect Drug Resist 11:77-86|
|Guo, Ming; Pegoraro, Adrian F; Mao, Angelo et al. (2017) Cell volume change through water efflux impacts cell stiffness and stem cell fate. Proc Natl Acad Sci U S A 114:E8618-E8627|
|Prakadan, Sanjay M; Shalek, Alex K; Weitz, David A (2017) Scaling by shrinking: empowering single-cell 'omics' with microfluidic devices. Nat Rev Genet 18:345-361|
|Costigliola, Nancy; Ding, Liya; Burckhardt, Christoph J et al. (2017) Vimentin fibers orient traction stress. Proc Natl Acad Sci U S A 114:5195-5200|
|Zaritsky, Assaf; Obolski, Uri; Gan, Zhuo et al. (2017) Decoupling global biases and local interactions between cell biological variables. Elife 6:|
Showing the most recent 10 out of 53 publications