Systems Biology of Sporulation in Bacillus Subtilis

描述（由申请人提供）：本提案旨在利用数学和统计学方法来理解枯草芽孢杆菌孢子形成实验系统中的发育基因控制。这是一个理想的系统，这样一个跨学科的方法，因为孢子形成是一个相对原始的发育系统，是非常容易的遗传学，生物化学和细胞学的工具。具体目标是了解孢子形成途径中的三种关键DNA结合蛋白（主调节因子）如何识别其靶点，并模拟控制孢子形成基因表达程序启动的电路。生物化学和分子遗传学实验将被设计和进行，以探测负责蛋白质结合的DNA序列特征，从而为计算策略的发展提供支持。反过来，计算预测将通过实验进行测试，以提供反馈来改进计算模型。还将开发模型来了解基因如何对关键主调节因子SpoOA的浓度做出不同的反应，并解释SpoOA的缓慢积累如何以及为什么在孢子形成启动中起关键作用。 孢子形成具有代表非常适合于定量方法的系统中的重要生物学问题的组合优点。因此，在这里取得的进展，在设计定量的方法来描述分子组成的孢子形成系统之间的相互作用，应作为一个模型的计算方法，以更复杂的生物系统。该提案的一个显着特点是，理论工作将与实验齐头并进，以便定量建模可以通过快速的经验反馈来提供信息，相反，数学模型可以指导实验和数据收集的设计，并且还可以建议对某些分析最有帮助且与现有数据最互补的数据类型。 这项研究将有助于更大的系统生物学领域，该领域试图定量描述“复杂的生物组织和过程的分子组成行为”（Mark Kirschner）。拟议的研究与人类健康有关，因为疾病通常涉及细胞调控成分之间相互作用的复杂网络的扰动，并将适用于设计定量方法来理解正常和异常细胞状态下的生物组织。对B的透彻理解。枯草芽孢杆菌孢子形成还可以为打击生物恐怖主义和由类似细菌如炭疽杆菌引起的疾病提供知识。

DESCRIPTION (provided by applicant): 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.