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）：此更新应用是我们成功生成大规模基因调节网络（GRN）来开发海胆胚胎内胚层的大规模基因调节网络的成功。从一开始，此GRN的进展取决于该赠款的主持人以及系统级实验方法开发的计算工具和方法。当我们最初申请这笔赠款时，内胚层GRN图处于初步结合状态。现在，它是胚胎规范的基因组源代码的经过实验测试，定义的逻辑图。如在进行报告中所述，我们在本项目的过程中建立了用于GRN的演示和分析方式。我们开发了一种非常有效的计算方法，用于识别顺式调节元件，以进行种间序列比较。后一种方法广泛使用，在我们的实验室中，已允许快速识别许多顺式调节元素，从而允许在GRN中产生的输入的DNA水平进行测试。现在，我们建议将GRN的计算开发提高到一个全新的水平。我们将产生一个交互式GRN模型，该模型将：（i）从领土功能（缩放）到特定输入的任何级别显示因果关系，以在给定的顺式调节元素（Zoom in）中； （ii）通过给定的胚胎空间结构域通过给定的时间通过给定的时间提供对交互图的访问； （iii）随着测量值的可用，允许将动力学关系的GRN纳入grn； （iv）表示顺式调节元素作为逻辑函数的组合； （v）提供了与相关基因组序列的联系，并与在顺式调节级别提出和认证的功能性GRN链接的实验证据。我们还建议使用与我们最近开发的Gene Cascade动力学模拟的方法对许多动力学预测进行建模和测试，并在进行中进行了描述。此外，我们打算完成对特定顺式调节系统的输入/输出动力学分析，作为GRN中顺式调节操作数学表示的演示项目。最后，我们建议确定给定的GRN电路元素，生成合成顺式调节构建体，其中将改变这些元素的正常操作，并将其重新引入胚胎，以确定我们对GRN的理解是否足以使胚胎过程重新设计。