The life of a cell in multicellular organisms is complex and proceeds through multiple stages, beginning with its “birth” from the division of preexisting cells, movement from its “birth” site to a distal target, differentiation into a form designed for a specialized task and then, finally, its death.  All of these events are in one way or another influenced by microtubules, intrinsically dynamic and structurally polar polymers of alpha/beta-tubulin further organized into higher order arrays that vary according to the immediate needs of the cell.  While probably best known as directional railways for the motor driven transport of intracellular cargos, microtubules also form the spindle apparatus that separates chromosomes and defines the site of cell cleavage during mitosis/meiosis, provide structural support for the formation of elongate cell shapes  and regulate the behaviors of other cytoskeletal networks, such as actin, through mechanisms that remain poorly understood. The broad objective of my research program is to identify the fundamental molecular mechanisms that goven the formation and function of the microtubule cytoskeleton and determine how these contribute to human health and disease.

Specific ongoing research projects include:

I) Determining the mechanisms of chromosome segregation.  The mitotic spindle is a self-organizing microtubule-based machine that segregates chromosomes into identical daughter nuclei during cell division.  Defects in spindle assembly and the movement of chromosomes on it give rise to cells with too many or two few chromosomes (aneuploidy) which is a hallmark of tumorigenesis.  Previous work from my laboratory has shown that the mitotic spindle moves chromosomes by a Pacman-Flux mechanism involving the coordinated activities of microtubule depolymerizing and severing enzymes (e.g. Rogers et al, Nature, 2004; Zhang et al, The Journal of Cell Biology, 2007, Rath and Sharp, Chromosome Research, 2011)

II) Determining the roles of microtubules in cell motility.  The ability of cells to migrate from their sites of origin to distal targets is fundamental to the development and maintenance of multicellular organisms.  Defects in cell migration have also been linked to numerous human pathologies ranging from mental retardation to cancer metastasis.  Decades of work have established that somatic cell motility is driven by a polarized actomyosin network that, among other things, promotes protrusion of the membrane at the cell front (leading edge) and contractility at the rear.  Much less is understood about the contributions of microtubules to these processes.  However, we recently showed that the microtubule severing enzyme, Katanin, localizes to the cell cortex and netatively regulates cell motility by suppressing actin-based protrusions (Zhang et al, Nature Cell Biology, 2011)  We have since identified a number of additional microtubule regulatory proteins (some of which are entirely uncharacterized in the literature) that control distinct parameters of cell movement.  Elucidation of the specific functions and mechanisms of action of these is a major current thrust of my research program.   

III)  Development of novel therapeutics.    We have found that specific microtubule regulatory proteins can be targeted to alter various aspects of human cell motility both in vitro and in vivo.  We are currently building on these findings to develop novel therapies to enhance wound healing, treat spinal cord injury and cardiovascular disease, and prevent cancer metastasis.  We are working closely with the Friedman, Nosanchuk and Zhou labs to develop and test nanoparticle-based approaches to manipulate the activiites of microtubule regulatory proteins in a clinical context.

1.         Zhang, D., et al., Drosophila katanin is a microtubule depolymerase that regulates cortical-microtubule plus-end interactions and cell migration. Nature Cell Biology, 2011. 13(4): p. 361-70.

2.         Sonbuchner, T.M., U. Rath, and D.J. Sharp, KL1 is a novel microtubule severing enzyme that regulates mitotic spindle architecture. Cell Cycle, 2010. 9(12): p. 2403-11.

3.         Rath, U., et al., The Drosophila kinesin-13, KLP59D, impacts Pacman- and Flux-based chromosome movement. Molecular Biology of the Cell, 2009. 20(22): p. 4696-705.

4.         Mennella, V., et al., Motor domain phosphorylation and regulation of the Drosophila kinesin 13, KLP10A. The Journal of Cell Biology, 2009. 186(4): p. 481-90.

5.         Fernandez, N., et al., A model for the regulatory network controlling the dynamics of kinetochore microtubule plus-ends and poleward flux in metaphase. Proceedings of the National Academy of Sciences of the United States of America, 2009. 106(19): p. 7846-51.

6.         Gomez-Ferreria, M.A., et al., Human Cep192 is required for mitotic centrosome and spindle assembly. Current Biology : CB, 2007. 17(22): p. 1960-6.

7.         Zhang, D., et al., Three microtubule severing enzymes contribute to the "Pacman-flux" machinery that moves chromosomes. The Journal of Cell Biology, 2007. 177(2): p. 231-42.

8.         Mennella, V., et al., Functionally distinct kinesin-13 family members cooperate to regulate microtubule dynamics during interphase. Nature Cell Biology, 2005. 7(3): p. 235-45.

9.         Rogers, G.C., et al., Two mitotic kinesins cooperate to drive sister chromatid separation during anaphase. Nature, 2004. 427(6972): p. 364-70.

1.         Zhang, D., et al., Drosophila katanin is a microtubule depolymerase that regulates cortical-microtubule plus-end interactions and cell migration. Nature Cell Biology, 2011. 13(4): p. 361-70.

2.         Sonbuchner, T.M., U. Rath, and D.J. Sharp, KL1 is a novel microtubule severing enzyme that regulates mitotic spindle architecture. Cell Cycle, 2010. 9(12): p. 2403-11.

3.         Rath, U., et al., The Drosophila kinesin-13, KLP59D, impacts Pacman- and Flux-based chromosome movement. Molecular Biology of the Cell, 2009. 20(22): p. 4696-705.

4.         Mennella, V., et al., Motor domain phosphorylation and regulation of the Drosophila kinesin 13, KLP10A. The Journal of Cell Biology, 2009. 186(4): p. 481-90.

5.         Fernandez, N., et al., A model for the regulatory network controlling the dynamics of kinetochore microtubule plus-ends and poleward flux in metaphase. Proceedings of the National Academy of Sciences of the United States of America, 2009. 106(19): p. 7846-51.

6.         Gomez-Ferreria, M.A., et al., Human Cep192 is required for mitotic centrosome and spindle assembly. Current Biology : CB, 2007. 17(22): p. 1960-6.

7.         Zhang, D., et al., Three microtubule severing enzymes contribute to the "Pacman-flux" machinery that moves chromosomes. The Journal of Cell Biology, 2007. 177(2): p. 231-42.

8.         Mennella, V., et al., Functionally distinct kinesin-13 family members cooperate to regulate microtubule dynamics during interphase. Nature Cell Biology, 2005. 7(3): p. 235-45.

9.         Rogers, G.C., et al., Two mitotic kinesins cooperate to drive sister chromatid separation during anaphase. Nature, 2004. 427(6972): p. 364-70.