Principles of Robust Developmental Patterning

稳健发展模式的原则

• 批准号: 7246588
• 负责人: FREDERIC Y.M. WAN
• 金额: $ 39.3万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7246588
• 关键词: Affect; Architecture; Biochemistry; Boat; Characteristics; Complex; Computing Methodologies; Congenital Abnormality; Data; Development; Diffuse; Drosophila sax protein; Elements; Engineering; Equilibrium; Evolution; Face; Failure; Feedback; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Enhancer Element; Glass; Human Development; Individual; Insecta; Ligands; Mathematics; Measures; Modeling; Mutation; Nutritional status; Organ Size; Organism; Pattern; Physiology; Process; Proteins; Regulation; Reporter Genes; Research Personnel; Resistance; Signal Transduction; System; Temperature; Testing; Time; Tissues; Uncertainty; Variant; Wing; Work; boating; cell growth; dosage; driving force; improved; in vivo; inhibitor/antagonist; morphogens; receptor; research study; response

DESCRIPTION (provided by applicant): The patterning of many developing tissues is controlled by gradients of morphogens. A significant challenge for morphogen gradients is to produce patterns that are not easily altered by genetic or environmental perturbations. The kinds of perturbations most likely to have driven the evolution of morphogen gradient systems are those that organisms face frequently: changes in biochemistry and physiology due to fluctuations in temperature, alterations in nutritional status, and the stochasticity of gene expression. Such perturbations are multifactorial, i.e. they affect many gene products and processes at the same time. Although investigators have recently begun to explore how morphogen gradients might withstand changes in the expression levels of single genes, our preliminary studies suggest that achieving robustness to multifactorial perturbations may require fundamentally different strategies. We will investigate this question through a combination of mathematical, computational and experimental approaches. Work will focus on one of the best-characterized morphogen gradients, the BMP gradient that patterns the larval insect wing disc. Initially, we will use both modeling and experiments to explore how this gradient responds to combinations of genetic perturbations, in order to identify rules that govern "robustness tradeoffs". Next, we will test the hypothesis that the architecture of the BMP gradient system reflects a drive toward optimization of robustness to temperature fluctuations. Third, we will identify ways in which the complex regulatory architecture of the Jbrin/cer gene, a key downstream target of the BMP gradient, contributes to robustness of the overall system. Finally, we will identify ways in which the deployment of two BMP ligands- decapentaplegic (Dpp) and glass bottom boat (Gbb) in the same gradient system also contributes to the robustness of patterning. Understanding the strategies used by morphogen gradient systems to withstand real-world perturbations is critical for explaining why human development proceeds so accurately most of the time, and is a necessary first step toward a general understanding of how and why failures of normal development, i.e. birth defects, arise.

描述（由申请人提供）：许多发育中的组织的模式受形态梯度的控制。形态学梯度的一个重大挑战是产生不容易通过遗传或环境扰动改变的模式。最有可能驱动形态梯度系统演变的扰动种类是生物体经常面对的扰动：由于温度的波动，营养状态的改变以及基因表达的随机性，生物化学和生理学的变化。这种扰动是多因素的，即它们同时影响许多基因产品和过程。尽管研究人员最近开始探索形态学梯度如何承受单基因表达水平的变化，但我们的初步研究表明，实现多因素扰动的鲁棒性可能需要从根本上进行不同的策略。我们将通过数学，计算和实验方法的结合来研究这个问题。工作将集中在特征最佳的形态学梯度之一上，该梯度是幼虫昆虫翼盘的BMP梯度。最初，我们将同时使用建模和实验来探讨该梯度如何响应遗传扰动的组合，以确定控制“稳健性权衡”的规则。接下来，我们将检验以下假设：BMP梯度系统的体系结构反映了朝着优化温度波动优化的动力。第三，我们将确定JBRIN/CER基因（BMP梯度的关键目标）的复杂调节结构有助于整体系统的鲁棒性。最后，我们将确定在同一梯度系统中部署两个BMP配体 - 脱牙和玻璃底船（GBB）的方式，也有助于构图的稳健性。了解形态学梯度系统用于承受现实世界扰动的策略对于解释为什么人类发展在大多数情况下如此准确地进行，这是朝着对正常发展的方式和为什么的一般理解（即出生缺陷）的一般理解所必需的第一步。