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

描述（由申请人提供）：形态发生信号传导构成关键细胞命运多样化机制之一，由此可扩散信号的梯度指定幼稚细胞场中的多种命运。虽然细胞外调控的形态梯度和直接受体和信号事件正在逐步的特点，我们的理解形态诱导细胞命运的方式仍然是非常不完整的。本研究的主要目的是分析形态发生梯度诱导细胞命运的机制。我们建议将联合收割机实验和建模方法相结合，以研究两种信号通路如何在发育组织的图案化中相互作用。我们将研究如何联合活动的表皮生长因子（EGF）受体和骨形态发生蛋白（BMP）受体系统模式的滤泡上皮细胞在发展中的果蝇卵，一个既定的模型的发展模式的形成。首先，我们将在这个系统中进行多变量分析的转录反应，使用三种不同的转录分析（微阵列，定量实时PCR，原位杂交）。其次，我们将使用这些实验的结果来计算探索发现的细胞外信号的信号串扰的目标的调节。第三，我们将制定机制模型的初始图案在这个系统中的事件，并使用这些模型来探索管道，基因的诱导的背腹侧胚胎轴的调节。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模式形成系统之一。EGFR和BMP信号转导失调与严重的发育缺陷和大量人类疾病相关。鉴于这些信号通路的高度保守性，我们的研究结果将提供定量的见解，在发展和成人组织的信号串扰的机制。

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.