Physiological Model of Gene Regulation in Drosophila

描述（由申请人提供）：相互作用的基因网络控制着各种基本的生物学过程，包括胚胎发育、细胞分裂和细胞死亡。了解控制发育的整个基因网络的功能是功能基因组学和系统生物学的核心问题。虽然解决这个问题的通用技术还不存在，但今天可以解决控制果蝇分割系统的基因网络。实现这一目标的研究计划是实验和计算建模的综合方案，该方案将用于表征在母体梯度中编码的位置信息转化为片段极性基因的精确和稳定表达的过程，所述片段极性基因在宽度为一个核的条纹中被缠绕和无翅。这个过程从不精确的母性线索中创造出一个极其精确的空间身体计划。包含相当大的噪声和个体之间的变化的早期模式被转换成具有很小变化的高度精确的晚期模式。提出的工作将导致在形态发生领域，决定果蝇分割的模式形成和纠错的现实和预测的理论。 我们的具体目标是：1）利用一系列化学动力学模型来理解在野生型和突变体中分段基因在wg和en表达起始时的典型表达和动力学。2)利用这些模型来更深入地了解在自然环境和压力下的鲁棒性3）对合子分割基因进行定量实时成像研究，并辅以来自突变体的固定组织数据。4.）开发新的工具来支持目标1-3，并通过FlyEx数据库将其与所有数据、模型和代码一起提供给科学界 公共卫生相关性： 该项目涉及基础科学与转化科学和医学的长期影响。它涉及发育的遗传学，对发育的科学理解是理解癌症和出生缺陷的先决条件。该项目还旨在准确理解发育中的渠道化，这是一个与伤口愈合和再生密切相关的“纠错”过程。

DESCRIPTION (provided by applicant): Networks of interacting genes control a variety of fundamental biological processes, including embryonic development, cell division, and cell death. Understanding the function of an entire network of genes which control development is a central problem of functional genomics and systems biology. Although general technology to solve the problem does not yet exist, it can be solved today for the network of genes which control the segmentation system of Drosophila melanogaster. The research plan to accomplish this goal is an integrated program of experimentation and computational modeling, which will be used to characterize the process by which positional information encoded in maternal gradients is transformed into precise and stable expression of the segment polarity genes engrailed and wingless in stripes one nucleus in width. This process creates an extremely precise spatial body plan from imprecise maternal cues. Early patterns containing considerable noise and variation between individuals are transformed into highly precise late patterns with little variation. The work proposed will result in a realistic and predictive theory of pattern formation and error correction in the morphogenetic field that determines Drosophila segmentation. Our specific aims are to 1) Make use of a family of chemical kinetic models to understand the typical expression and the dynamics of the segmentation genes in wild type and mutants up the initiation of wg and en expression. 2) Exploit these models to gain deeper understanding of robustness, both in a natural context and under stress 3) Perform quantitative live imaging studies of zygotic segmentation genes, supplemented by fixed tissue data from mutants. 4.) Develop new tools to support Aims 1-3 and make them, together with all data, models, and code available to the scientific community through the FlyEx database PUBLIC HEALTH RELEVANCE: This project concerns basic science with long term implications for translational science and medicine. It is concerned with the genetics of development, the scientific understanding of which is a precondition for understanding cancer and birth defects. The project also aims at a precise understanding of canalization in development, an "error correction" process that is closely related to wound healing and regeneration.