This proposal is an application for a competitive revision to grant 5 R01 GM082834-02 """"""""Small molecule probes of cytokinesis"""""""" in response to Notice Number NOT-OD-09-058 """"""""NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications"""""""". How cells regulate and execute cytokinesis, the final step in cell division, remain major unsolved questions in basic biology. Our long-term goal is the systematic dissection of temporal and spatial control during cytokinesis. It has been challenging to study cytokinesis with traditional methods because it is a rapid process and many key cytokinesis proteins also perform important functions earlier in the cell cycle. Small molecules, which act rapidly and with high temporal control, are ideal tools to study cytokinesis. We discovered several novel small molecule inhibitors of cytokinesis, and the parent grant focuses on understanding the mechanism of three of these compounds. To increase the pool of small molecule tools, here we propose to discover molecules that target regulatory pathways in cytokinesis, specifically the Rho pathway. We will use RNAi to create sensitized cells that will allow us to detect specific inhibitors and identify small molecule targets by a straightforward approach similar to epistasis analysis. We have designed an interdisciplinary approach, combining chemistry, imaging techniques and biochemistry to use our small molecules to probe the role of the Rho pathway in cytokinesis. This proposal combines the development of new technological approaches with simultaneous application to a fundamental and important biological question.
Many mechanisms underlying cytokinesis, the final step in cell division, remain poorly understood. Failed cell division is causal or contributory in diseases such as cancer. Small molecules that specifically target cytokinesis and in particular the Rho signaling pathway, are important tools to study the underlying biology of cell division and could catalyze the discovery of therapeutic drugs to treat cancer.
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