Genome wide analysis and modeling of signal integration in the Drosophila ovary

描述（由申请人提供）：形态发生信号构成了细胞命运多样化的关键机制之一，其中扩散信号的梯度指定了幼稚细胞领域的多种命运。虽然细胞外对形态发生梯度的调控以及对直接受体和信号事件的调控正逐渐得到表征，但我们对形态发生诱导细胞命运的方式的理解仍然非常不完整。分析形态梯度诱导细胞命运的机制是本研究的主要目标。我们建议结合实验和建模方法来研究两个信号通路如何在发育组织的模式中相互作用。我们将研究表皮生长因子（EGF）受体和骨形态发生蛋白（BMP）受体系统的联合活动如何影响发育中的果蝇卵中的滤泡上皮，这是一个已建立的发育模式形成模型。首先，我们将对该系统的转录反应进行多变量分析，使用三种不同的转录分析方法（微阵列、实时定量PCR和原位杂交）。其次，我们将利用这些实验的结果来计算探索细胞外信号对信号串扰靶点的调节。第三，我们将建立该系统中初始模式事件的机制模型，并利用这些模型探索对诱导背腹侧胚胎轴至关重要的基因Pipe的调控。我们期望，作为这些实验、建模和计算研究的结果，滤泡上皮将成为最具特征的图案形成系统之一。EGFR和BMP信号的失调与严重的发育缺陷和大量的人类疾病有关。鉴于这些信号通路的高度保守性，我们的研究结果将为发育和成年组织中信号串扰的机制提供定量的见解。

DESCRIPTION (provided by applicant): Morphogenetic signaling constitutes one of the key cell fate diversification mechanisms whereby a gradient of a diffusible signal specifies multiple fates in a field of naive cells. While the extra cellular regulation of morphogen gradients and of the immediate receptor and signaling events are becoming progressively characterized, our understanding of the ways by which morphogens induce cell fates is still very incomplete. Analysis of the mechanisms of cell fate induction by morphogen gradients is the main goal of this proposal. We propose to combine experimental and modeling approaches to investigate how two signaling pathways interact in patterning of a developing tissue. We will study how the joint activities of the Epidermal Growth Factor (EGF) receptor and Bone Morphogenetic Protein (BMP) receptor systems pattern the follicular epithelium in the developing Drosophila egg, an established model of developmental pattern formation. First, we will carry out a multivariable analysis of transcriptional responses in this system, using three different transcriptional profiling assays (micro arrays, quantitative real-time PCR, and in situ hybridization). Second, we will use the results of these experiments to computationally explore the regulation of discovered targets of signaling crosstalk by extra cellular signals. Third, we will formulate mechanistic models for the initial patterning events in this system and use these models to explore the regulation of Pipe, the gene essential for the induction of the dorsoventral embryonic axis. We expect that, as a result of these experimental, modeling, and computational studies, the follicular epithelium will become one of the best-characterized pattern formation systems. Deregulated EGFR and BMP signaling are associated with severe developmental defects and a large number of human diseases. Given the highly conserved nature of these signaling pathways, our results will provide quantitative insights into the mechanisms of signaling crosstalk in developing and adult tissues.