Computational Model of Gene Regulatory Program

基因调控程序的计算模型

• 批准号: 7036506
• 负责人: ERIC H DAVIDSON
• 金额: $ 36.94万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036506
• 关键词: computer simulation; developmental genetics; early embryonic stage; endoderm; genetic models; genetic regulatory element; invertebrate embryology; mesoderm; model design /development; sea urchins; transcription factor

DESCRIPTION (provided by applicant): This renewal application follows on our success in generating a large-scale gene regulatory network (GRN) for development of the endomesoderm of the sea urchin embryo. Progress on this GRN from the beginning depended on computational tools and approaches developed under the auspices of this grant, as well as on system-level experimental approaches. When we originally applied for this grant, the endomesoderm GRN map was in a preliminary state of coalescence; now it is a well developed, experimentally testable, defined logic map of the genomic source code for embryonic specification. As described in Progress Report, we built the mode of presentation and analysis used for the GRN in the course of this project; and we developed from scratch an extremely effective computational approach to interspecific sequence comparison for the purpose of identifying cis-regulatory elements. This latter method is in wide use, and in our lab has permitted rapid identification of many cis-regulatory elements, thereby permitting test, at the DNA level, of the inputs produced in the GRN. We now propose to carry out computational development of the GRN to an entirely new level. We will produce an interactive GRN model that will: (i) display causal interrelations at any level from territorial functionalities (zoom out) to specific inputs into given cis-regulatory elements (zoom in); (ii) provide access to the interaction map, via given genes, via given times in development, via given embryonic spatial domains; (iii) permit incorporation into the GRN of kinetic relationships, as measurements become available; (iv) represent cis-regulatory elements as combinations of logic functions; and (v)provide links to relevant genomic sequence and to experimental evidence on which functional GRN linkages have been proposed and authenticated at the cis-regulatory level. We also propose to model and test many kinetic predictions by means of time course measurements, using approaches similar to those of our recently developed gene cascade kinetic simulations, described also in Progress Report. In addition we intend to complete an input/output kinetic analysis of a specific cis-regulatory system, as a demonstration project for mathematical representation of cis-regulatory operations within the GRN. Finally, we propose to identify given GRN circuit elements, produce synthetic cis-regulatory constructs in which normal operation of these elements will be altered, and reintroduce them into the embryo to determine whether our understanding of the GRN is sufficient to permit reengineering of the embryonic process.

描述（由申请人提供）：本更新申请是继我们成功生成用于海胆胚胎内中胚层发育的大规模基因调控网络（GRN）之后的。该 GRN 的进展从一开始就依赖于在这笔赠款的支持下开发的计算工具和方法，以及系统级实验方法。当我们最初申请这项资助时，内中胚层 GRN 图谱处于初步合并状态；现在它是一个开发良好、可通过实验测试、定义胚胎规范基因组源代码的逻辑图。正如进度报告中所述，我们在本项目过程中构建了GRN的呈现和分析模式；我们从头开始开发了一种极其有效的计算方法来进行种间序列比较，以识别顺式调控元件。后一种方法得到广泛使用，在我们的实验室中，可以快速识别许多顺式调控元件，从而可以在 DNA 水平上测试 GRN 中产生的输入。我们现在建议将 GRN 的计算开发提升到一个全新的水平。我们将生成一个交互式 GRN 模型，该模型将：（i）显示从区域功能（缩小）到给定顺式监管元素的特定输入（放大）的任何级别的因果关系； (ii) 通过给定的基因、给定的发育时间、给定的胚胎空间域提供对相互作用图的访问； (iii) 当测量可用时，允许将动力学关系纳入 GRN； (iv) 将顺式监管要素表示为逻辑功能的组合； (v) 提供相关基因组序列的链接以及已在顺式监管水平上提出和验证功能性 GRN 连接的实验证据。我们还建议通过时间过程测量来建模和测试许多动力学预测，使用类似于我们最近开发的基因级联动力学模拟的方法，也在进度报告中进行了描述。此外，我们打算完成特定顺式调节系统的输入/输出动力学分析，作为 GRN 内顺式调节操作的数学表示的示范项目。最后，我们建议识别给定的GRN电路元件，产生合成的顺式调节结构，其中这些元件的正常运作将被改变，并将它们重新引入胚胎中，以确定我们对GRN的理解是否足以允许对胚胎进行重新设计过程。