Microtubules are polymers that serve critical roles in establishing and maintaining cellular architecture. Microtubules are the target of important anticancer drugs such as the vinca alkaloids and taxol (paclitaxel), and are thought to play a role in neurodegenerative diseases such as Alzheimer's. Microtubules are dynamic polymers of the protein tubulin, a GTPase, and the energy of GTP hydrolysis drives dynamic instability whereby microtubules spontaneously switch between periods of polymerization and rapid depolymerization. This behavior is regulated by cells to achieve rapid restructuring of the cytoskeleton. To better understand dynamic instability we have developed methods to track microtubule polymerization with nanometer scale resolution, thereby revealing fundamental behaviors that were not resolved by traditional approaches. This work has led to a fundamental reassessment of the molecular mechanics underlying dynamic instability, and provides important insight into the mechanisms by which drugs and microtubule associated proteins can regulate microtubule dynamics. Here we combine nanometer resolution studies of microtubule dynamics with molecular modeling to understand the detailed actions of taxol at clinically relevant doses, and the microtubule regulating protein tau, which plays an important role in Alzheimer's and other neurodegenerative diseases.

Public Health Relevance

The results of proposed studies will yield a better understanding of the mechanics of microtubule assembly, and how these are altered by effective chemotherapy drugs, and the tau protein, which plays a central role in Alzheimer's and other neurodegenerative diseases. In addition to providing a better understanding of processes important for understanding and treating cancer and neurodegenerative disease, broad impact across the biomedical sciences will be achieved by advancing transformative technology for studying biological mechanics with nanometer scale precision.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM076177-06
Application #
8518368
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Gindhart, Joseph G
Project Start
2007-09-21
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
6
Fiscal Year
2013
Total Cost
$297,927
Indirect Cost
$79,724
Name
University of Michigan Ann Arbor
Department
None
Type
Schools of Engineering
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Prahl, Louis S; Castle, Brian T; Gardner, Melissa K et al. (2014) Quantitative analysis of microtubule self-assembly kinetics and tip structure. Methods Enzymol 540:35-52
Aiken, Jayne; Sept, David; Costanzo, Michael et al. (2014) Genome-wide analysis reveals novel and discrete functions for tubulin carboxy-terminal tails. Curr Biol 24:1295-303
Gardner, Melissa K; Charlebois, Blake D; Janosi, Imre M et al. (2011) Rapid microtubule self-assembly kinetics. Cell 146:582-92
Mogilner, Alex; Odde, David (2011) Modeling cellular processes in 3D. Trends Cell Biol 21:692-700
Charlebois, Blake D; Kollu, Swapna; Schek, Henry T et al. (2011) Spindle pole mechanics studied in mitotic asters: dynamic distribution of spindle forces through compliant linkages. Biophys J 100:1756-64
Gupta, Kamlesh K; Paulson, Benjamin A; Folker, Eric S et al. (2009) Minimal plus-end tracking unit of the cytoplasmic linker protein CLIP-170. J Biol Chem 284:6735-42
Gardner, Melissa K; Hunt, Alan J; Goodson, Holly V et al. (2008) Microtubule assembly dynamics: new insights at the nanoscale. Curr Opin Cell Biol 20:64-70
Chan, Clarence E; Odde, David J (2008) Traction dynamics of filopodia on compliant substrates. Science 322:1687-91
Lorch, David P; Lindemann, Charles B; Hunt, Alan J (2008) The motor activity of mammalian axonemal dynein studied in situ on doublet microtubules. Cell Motil Cytoskeleton 65:487-94
Schek 3rd, Henry T; Gardner, Melissa K; Cheng, Jun et al. (2007) Microtubule assembly dynamics at the nanoscale. Curr Biol 17:1445-55