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

果蝇卵巢信号整合的全基因组分析和建模

• 批准号: 7130302
• 负责人: Stanislav Y. Shvartsman
• 金额: $ 24.99万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7130302
• 关键词: Drosophilidae; arthropod genetics; bioinformatics; biological signal transduction; bone morphogenetic proteins; computational biology; developmental genetics; epidermal growth factor; gene expression profiling; genetic regulation; genetic transcription; growth factor receptors; in situ hybridization; microarray technology; model design /development; ovary; polymerase chain reaction; protein protein interaction; receptor expression; reproductive development

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.

描述（由申请人提供）：形态发生信号构成了关键细胞命运多样化机制之一，在该机制中，扩散信号的梯度指定了幼稚细胞领域中的多个命运。虽然形态梯度的额外细胞调节以及直接受体和信号事件的逐渐表征，但我们对形态剂诱导细胞命运的方式的理解仍然非常不完整。该提议的主要目标是对形态学梯度诱导细胞命运诱导的机制的分析。我们建议结合实验和建模方法，以研究两个信号通路在发育组织的模式下如何相互作用。我们将研究表皮生长因子（EGF）受体和骨形态发生蛋白（BMP）受体系统的关节活性如何模式发展果蝇卵中的卵泡上皮，这是一种已建立的发育模式形成模型。首先，我们将使用三种不同的转录分析测定法（微阵列，定量实时PCR和原位杂交）对该系统中转录响应进行多变量分析。其次，我们将使用这些实验的结果来计算通过额外的细胞信号来探索发现的信号串扰的靶标。第三，我们将为该系统中的初始图案事件制定机械模型，并使用这些模型探索管道调节，这对于诱导背腹胚胎轴的诱导至关重要。我们预计，由于这些实验，建模和计算研究，卵泡上皮将成为特征最佳的模式形成系统之一。 EGFR和BMP信号传导与严重的发育缺陷和大量人类疾病有关。鉴于这些信号通路的高度保守性，我们的结果将提供定量的见解，以了解发育和成人组织中信号传导串扰的机制。