The active, contractile, and remodeling nature of the cytoskeleton is central to many cellular activities. No model yet exists, however, for quantifying these phenomena. The objective of this research is to translate discrete nano-scale molecular events like actin-myosin interaction into a macro-scale at which the cellular contractility and remodeling operate. A quantitative model of cell contractility will be developed reflecting the heterogenous, interconnected and remodeling nature of the cytoskeleton. Such a model is crucial to interpreting the micro-scale and macro-scale mechanical behavior of the cell that is complicated by the long-range interconnections and reorganizations characteristics of the cytoskeleton.
The proposed model is crucial to interpreting the micro-scale and macro-scale cytoskeletal functions that are complicated by the long-range interconnections and reorganizations characteristics of the cytoskeleton. The experimental observations on micro- and macro-scale cytoskeletal mechanics will be interpreted in the context of the heterogeneous, interconnected and remodeling character of the cytoskeleton. While a model of more complex cell processes such as mechanotransduction and migration are beyond the immediate scope of this research, the tools developed here will subsequently aide the research community in addressing other fundamentally important issues in a manner that cannot be explored systematically and quantitatively by experiments alone. The proposed model will offer a necessary tool for advancing our understanding of a key step in cellular mechanosensing and mechanotransduction, and has therefore a strong transformative potential for discovering new strategies to mitigate many diseases where the interplay of mechanics and biochemistry are critical (e.g. atherosclerosis, calcific aortic stenosis, cancer, ...)
On an outreach level, the PI plans to disseminate the research through a website dedicated to cellular and molecular mechanisms. In addition, the PIs plan to develop new courses and to broaden the participation of students from underrepresented groups.
PI: Mofrad (Award #:CBET-0829205) (Start: September 2008-August 2012) Aim 1) To develop a model of myosin interacting with cytoskeletal actin network at the macro-molecular scale, at which the interaction dynamics can be accurately captured; Aim 2) To incorporate the macro-molecular scale model into the cell-scale by a reduced-integration, multi-scale formulation to show formation of stress-fibers as channel-like actin bundles in a contractile cell, and Aim 3) To experimentally verify the model against stress-fiber patterns formed in cells contracting in a micro-well with micro-patterned fibronectin attachments. RESULTS SUMMARY & HIGHLIGHTS (September 2008-August 2012) Intellectual Merits: - A new approach was developed to model the Brownian dynamics of semiflexible filaments (Chandran & Mofrad 2009 Phys Rev E; Chandran & Mofrad 2010 Phys Rev E; Karimi et al. PRL. 2011). - Developed a simple coarse-grained model of the myosin forces involved in stress fiber formation (Chandran et al. 2009 Cell & Mol. Bio). - Investigated the molecular mechanics of actin binding proteins, α-Actinin and filamin, which serve as a scaffold and maintain dynamic actin filament networks (Golji et al. 2009 PLoS Comp Bio; Chen et al. Biophys. 2009). - Developed a computational modeling of microtubule bundles (Peter and Mofrad 2012). - Showed the significance of microtubule flexural behavior in cytoskeletal mechanics (Mehrbod and Mofrad 2011) - Explored the behavior of microtubular bundles under tension and compression Broader and Transformative Impacts: The models developed in this work have helped in interpreting the micro-scale and macro-scale cytoskeletal functions that are complicated by the long-range interconnections and reorganizations characteristics of the cytoskeleton. 3 NEW COURSES FOR UC Berkeley UGrad and Grad BIOE112 – Molecular Cell Biomechanics (developed and instituted Spring 2009—taken by 35 undergraduate students) BIOE215 – Mechanobiology of the Cell: Dynamics of the Cytoskeleton and Nucleus (developed and instituted Spring 2009—taken by 8 graduate students) ME120 – Computational Biomechanics Across Multiple Scales (new course to be initiated in spring 2013) 11 JOURNAL PUBLICATIONS M. Soheilypour, Peyro M, Peter SJ, Mofrad MRK. Buckling Behavior of Microtubule Bundles. Submitted. Karimi R, Alam MR, Mofrad MRK (2012). Hydrodynamic interactions significantly alter the dynamics of actin cytoskeleton. Submitted. Holt BD, Shams H, Horst TA, Basu S, Rape DA, Wang Y-L, Rohde GK, Mofrad MRK, Islam MF and Dahl KN (2012). Altered Cell Mechanics from the Inside: Dispersed Single Wall Carbon Nanotubes Integrate with and Restructure Actin. Journal of Functional Biomaterials, 3: 398-417. Peter SJ, Mofrad MRK (2012). Computational Modeling of Axonal Microtubule Bundles under Tension. Biophysical Journal, 102(3):749-757. Mehrbod M, Mofrad MRK. On the Significance of Microtubule Flexural Behavior in Cytoskeletal Mechanics. PLoS One. 2011. 6(10):e25627. Jamali Y, Azimi M, Mofrad MR. (2010) A sub-cellular viscoelastic model for cell population mechanics. PLoS One. 5(8). pii: e12097. Chandran PL, Mofrad MR (2010). Averaged implicit hydrodynamic model of semiflexible filaments. Phys Rev E Stat Nonlin Soft Matter Phys. 81(3 Pt 1):031920. Epub 2010 Mar 26. Golji J, Collins R, Mofrad MR (2009). Molecular Mechanics of the alpha-Actinin Rod Domain: Bending, Torsional, and Extensional Behavior. PLoS Comput Biol. 2009 May;5(5):e1000389. Chandran PL, Wolf CB, Mofrad MRK (2009). Band-like Stress Fiber Propagation in a Continuum and Implications for Myosin Contractile Stresses. Cell. & Molecular Bioeng. 2(1):13-27. Mofrad MRK (2009). Rheology of the cytoskeleton, Ann. Rev. of Fluid Mechanics. 41:433-453 Chandran PL, Mofrad MR. (2009) Rods-on-string idealization captures semiflexible filament dynamics, Phys Rev E 79(1 Pt 1):011906.
