Cell Cycle Regulatory Networks: An Integrative Approach.

Type of Award: Catalyst
Date Awarded: November 2009
Award End Date: October 2011
Amount Awarded: $ 188,000.00
PI(s): Alexander Minella, MD, Northwestern University; Marsha Rosner, PhD, The University of Chicago; Robert Rosner, PhD, The University of Chicago;

Abstract: Appropriate regulation of cell division is necessary for the normal growth and differentiation of mammalian cells. Loss of cell division controls causes abnormal proliferation, chromosome damage, and, ultimately, progression to diseases such as cancer. Therefore, it is critical for cells to maintain rigorous control of key transition points in the cell division cycle, such as the initiation of DNA replication. In early phases of the cell cycle leading to DNA replication initiation, this control is accomplished in large part by proteins called cyclins and cyclin-dependent kinases. These proteins are necessary for initiating DNA replication and driving cell cycle progression in all organisms, and importantly, they are normally regulated by complex networks that control their activity. To develop a better understanding how diverse regulatory controls on cyclins function together in different cellular contexts, we propose a novel integrative approach that utilizes a multi-disciplinary team of researchers based at Northwestern University and The University of Chicago. We will first develop computational models focused upon the regulation of cyclin E, a key regulator of early cell cycle progression in early mammalian cells. We hypothesize that we can utilize these models to accurately simulate the complex regulation of cyclin E activity. Next, we will use living cell imaging techniques to obtain key data at the single cell level, following experimental manipulations, in order to test and refine our computational models. With these studies, our group aims to develop a robust system, which can be used for generating testable hypotheses to study complexly-regulated components of not only cell cycle machinery but many other cellular processes. Current experimental approaches used by individual laboratories typically focus on studying how genes and proteins are regulated by a single set of molecular controls. We believe the results of our work will enable more unbiased approaches for identifying critical regulatory components, among many, of a given protein within a specific cellular context, which may ultimately be useful in such applications as drug design and molecular diagnostics.