Cell and Chemical Biology of Microtubules

Project Summary/Abstract Microtubules are long, dynamic filaments made of tubulin protein which physically organize most human cells, with prominent roles in cell division and neurons. We will investigate the cell- and chemical biology of microtubules using microscopy, biochemistry and genetics. We seek to answer fundamental questions about microtubule organization and function and to generate knowledge relevant to treating human diseases where microtubules play a role. We will analyze the physical mechanisms cells use to divide using frog eggs (Xenopus) as a model system. A key unanswered question is how different components of the cell interact mechanically to promote accurate division. This work will help us understand mistakes in cell division that give rise to birth defects and cancer. We will image individual growing microtubules in cells and frog egg extracts and measure sideways movement of growing tips, which will reveal previously hidden physical forces that act on them and help us understand microtubule organization. We are interested in developing drugs that perturb mitosis in certain cancers but normal cells, which may open new avenues to treatment. We will target a kinase called VRK1, which is selectively essential for mitosis in glioblastomas. We are interested in how microtubules become damaged in disease states such as inflammation, cancer and neurodegeneration. We hypothesis that tubulin is chemically damaged by reactive fragments of cellular lipids and that Stathmin- 1 protein protects cells by sequestering damaged tubulin. We will test this idea using biochemistry and microscopy of cultured cells and de-identified human disease biopsies. A related protein called Stathmin-2 protects the health of motor neurons and its loss can cause ALS. We will analyze how sthamin-2 protects neurons, hoping to generate knowledge relevant to disease-modifying treatments of ALS.