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

描述(申请人提供)：形态发生信号构成了关键的细胞命运多样化机制之一，由此可扩散信号的梯度决定了幼稚细胞领域中的多个命运。虽然形态原梯度和直接受体和信号事件的细胞外调节逐渐被表征，但我们对形态原诱导细胞命运的方式的理解仍然很不完整。分析形态原梯度诱导细胞命运的机制是这一建议的主要目标。我们建议结合实验和建模方法来研究两个信号通路在发育中的组织模式中是如何相互作用的。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在发育中的果蝇卵中形成毛囊上皮，这是一个已建立的发育模式形成的模型。首先，我们将在这个系统中使用三种不同的转录图谱分析方法(微阵列、定量实时聚合酶链式反应和原位杂交)对转录反应进行多变量分析。其次，我们将使用这些实验的结果来计算探索细胞外信号对已发现的信号串扰目标的调节。第三，我们将为该系统中最初的构图事件建立机制模型，并使用这些模型来探索PIPE的调控，PIPE是诱导背腹胚轴所必需的基因。我们期望，作为这些实验、建模和计算研究的结果，卵泡上皮将成为最具特征的模式形成系统之一。去调控的EGFR和BMP信号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，我们的结果将为发育中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.