This proposal aims to bring the methods of mathematics and statistics to bear on understanding developmental gene control in the experimental system of sporulation in the bacterium Bacillus subtilis. This is an ideal system for such an interdisciplinary approach because sporulation is a relatively primitive developmental system and is highly accessible to the tools of genetics, biochemistry and cytology. The specific goals are to understand how three key DNA-binding proteins (master regulators) in the sporulation pathways recognize their targets, and to model the circuitry that governs the initiation of the program of sporulation gene expression. Biochemical and molecular genetic experiments will be designed and conducted to probe DNA sequence features responsible for protein binding so as to feed to the development of computational strategies. In turn computational predictions will be tested experimentally to provide feedbacks to improve computational models. Models will also be developed to understand how genes respond differently to the concentration of a key master regulator SpoOA, and to explain how and why the slow accumulation of SpoOA plays a key role in the sporulation initiation. Sporulation has the combined virtues of representing a significant biological problem in a system that is well suited to quantitative approaches. Hence, the progress made here in devising quantitative methods to describe the interactions among the molecular constituents of the sporulation system should serve as a model for computational approaches to more complicated biological systems. A distinctive feature of this proposal is that the theoretical work will be carried out hand-in-hand with experimentation so that quantitative modeling can be informed by rapid empirical feedback and, conversely, mathematical models can guide the design of experiments and data collection, and can also suggest the types of data that are most helpful for certain analyses and most complementary to existing data. The research will contribute to the larger field of systems biology, which attempts to describe quantitatively """"""""the behavior of complex biological organization and processes in terms of the molecular constituents"""""""" (Mark Kirschner). The proposed research is relevant to human health because disease typically involves perturbations to the complex web of interactions among cellular regulatory components and will be applicable to devising quantitative approaches to understanding biological organization in normal and abnormal cellular states. A thorough understanding of B. subtilis sporulation can also provide knowledge for combating bio-terrorism and diseases that are caused by similar bacteria, such as Bacillus anthracis.
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