The stable propagation of our genomes requires the accurate segregation of replicated chromosomes and the proper cleavage of a cell into two daughters. These processes depend on the formation a bipolar spindle before anaphase and a central spindle (or midzone) once anaphase starts. Our long-term goal is to examine how these complex and dynamic microtubule-based structures assemble and function. As steps to achieving this goal, we propose an interdisciplinary approach, focusing on kinesin-5 and Polo-like kinases (Plks), evolutionarily conserved proteins required for cell division. Chemical inhibitors for Eg5 (the vertebrate kinesin- 5) and Plks are being evaluated as drugs for cancer therapy. Our studies will provide insight into the cell division functions of these proteins and also impact the development of drugs that target them. In this project we will: (i) Examine the motility of single Eg5 molecules between two microtubules, (ii) Characterize how Eg5's structural organization influences its motile properties and function, (iii) Examine the role of Polo-like kinases in regulating microtubule dynamics during cell division, (iv) Characterize Polo-like kinase substrates that regulate microtubule dynamics in dividing cells, (v) Examine the role of Polo-like kinases in initiating cytokinesis. Errors in cell division have been linked to developmental defects and diseases in humans. Our studies will provide insight into the mechanisms that ensure the fidelity of this basic cellular process. The application is submitted in response to Notice Number (NOT-OD-09-058, Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications).
Errors in cell division are linked to developed defects and disease in humans. Our project focuses on examining molecular mechanisms that ensure the fidelity of cell division and has the potential to impact therapeutic strategies based on targeting cell division.
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