Principles of Robust Developmental Patterning

稳健发展模式的原则

• 批准号: 7144549
• 负责人: FREDERIC Y.M. WAN
• 金额: $ 39.59万
• 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/7144549
• 关键词: Drosophilidae; biological signal transduction; biological transport; cell communication molecule; cell component structure /function; developmental genetics; genetic transcription; histogenesis; interdisciplinary collaboration; intermolecular interaction; invertebrate embryology; mathematical model; model design /development; receptor binding; receptor expression; tissue /cell culture

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 1 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 2 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）：许多发育中组织的图案化由形态发生素的梯度控制。形态发生梯度的一个重大挑战是产生不容易被遗传或环境扰动改变的模式。最有可能驱动形态梯度系统进化的扰动是生物体经常面临的那些：由于温度波动引起的生物化学和生理学变化，营养状况的改变以及基因表达的随机性。这种扰动是多因素的，即它们同时影响许多基因产物和过程。虽然研究人员最近开始探索形态梯度如何承受单个基因表达水平的变化，但我们的初步研究表明，要实现对多因素扰动的鲁棒性，可能需要采取根本不同的策略。我们将通过数学、计算和实验方法的结合来研究这个问题。工作将集中在一个最好的特点形态梯度，BMP梯度图案的幼虫昆虫翅盘。最初，我们将使用建模和实验来探索这种梯度如何响应遗传扰动的组合，以确定管理“鲁棒性权衡”的规则。接下来，我们将测试BMP梯度系统的架构反映了对温度波动鲁棒性优化的驱动力的假设。第三，我们将确定的方式，其中复杂的调控结构的JAPONIX/cer基因，一个关键的下游目标的BMP梯度，有助于整个系统的鲁棒性。最后，我们将确定在同一梯度系统中部署2种BMP配体-十肢麻痹（Dpp）和玻璃底船（Gbb）的方法也有助于图案化的鲁棒性。了解形态发生梯度系统抵御现实世界扰动的策略对于解释为什么人类发育在大多数时间都如此准确至关重要，并且是全面了解正常发育失败（即出生缺陷）的原因和原因的必要的第一步。