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Vascular smooth muscle cells must be able to both sense and respond to force stimuli, as well as bear and transmit stresses. Failure to either properly sense or respond to external stresses is known to lead to several pathological cardiovascular conditions, including hypertension and smooth muscle hypertrophy. Actin and its associated actin-binding proteins (ABPs) are key mechanical components of the cytoskeleton and are able to dynamically modulate cell mechanics through remodeling. Characterizing actin in the presence of ABPs and understanding how these regulate actin filament mechanics is a crucial first step in understanding the role of actin in vascular response to shear and pressure. My research focuses on characterizing actin and cell mechanics and dynamics on scales ranging from the single filament to the entire cytoskeleton.
Actin mechanics and stability
In my research, I study the mechanics of actin filaments with and without ABPs, quantified through the filament flexural rigidity and mechanical stability. Flexural rigidity is quantified using results derived from the wormlike chain model on fluorescently labeled actin filaments undergoing thermal fluctuations. I also employ shearing assays of actin filaments to assess filament stability. My latest research on single actin filament mechanics has focused on basic calponin, a smooth muscle ABP believed to play a role in smooth muscle cytoskeletal regulation. I recently demonstrated the mechanical effects of calponin on single actin filaments in terms of the filaments’ flexural rigidity and shear susceptibility. I also collaborate with the Weitz lab at Harvard University to characterize the effects of calponin on the mechanics of crosslinked actin networks using bulk rheology. Current work aims to elucidate the effects of the ABPs calponin and tropomyosin in this system more closely mimicking a cytoskeletal actin network.
Actin assembly and dynamics
In addition to actin mechanics, actin assembly and dynamics are also closely regulated and important parameters governing the overall cytoskeletal behavior. In collaboration with Dr. Chih-Lueh Albert Wang (http://www.bbri.org/index.php/our_scientists/articles/wang.html), I am studying the effects of H32K, a C-terminal fragment of the smooth muscle protein caldesmon, on actin structure and dynamics. We recently demonstrated that H32K prolongs a nascent state of polymerizing actin without altering the growth dynamics. This nascent state is hypothesized to alter the interactions of F-actin with other ABPs. One key ABP of interest is the protein complex Arp2/3, which nucleates and branches actin. Together with Dr. Wang and Eliza Morris of the Weitz lab at Harvard University (http://weitzlab.seas.harvard.edu/research/morris-eliza.html), I recently demonstrated that H32K-stabilized nascent actin filaments more readily bind Arp2/3 and form branched structures. My main techniques include total internal reflectance fluorescence microscopy (TIRFM), which is designed and built by myself and others in our lab, and confocal microscopy.
In collaboration with Ming Guo of the Weitz lab at Harvard University (http://weitzlab.seas.harvard.edu/research/guo-ming.html), I study the intracellular mechanics of whole cells using microrheological techniques. Optical tweezers designed and constructed by myself and others in our lab are used to manipulate injected beads in the cell interior to quantify the local mechanical environment in terms of the storage and loss moduli. Our recent work on A7 cells has elucidated how the cell, despite being a largely elastic material, can allow passive transport of objects much larger than the network mesh size.
Ph.D. candidate, Physics
M.A. , Physics
B.S., Physics and Maths
MH Jensen*, EJ Morris*, R Huang*, G Rebowski, R Dominguez, DA Weitz, JR Moore, C-LA Wang. (2012) The conformational state of actin filaments regulates branching by actin-related protein 2/3 (Arp2/3) complex. Journal of Biological Chemistry (accepted, published online ahead of print).
MH Jensen, J Watt, JL Hodgkinson, C Gallant, S Appel, M El-Mezgueldi, TE Angelini, KG Morgan, W Lehman, JR Moore. (2012) Effects of basic calponin on the flexural mechanics and stability of F-actin. Cytoskeleton 69:49-58.
A Collins, R Huang, MH Jensen, J Moore, W Lehman, C-LA Wang. (2011) Structural studies on maturing actin filaments. BioArchitecture 1:127-133.
MH Jensen, EJ Morris, AC Simonsen. (2007) Domain shapes, coarsening, and random patterns in ternary membranes. Langmuir 23:8135-8141.