Growth regulation by the Fat signaling pathway

描述（由申请人提供）：本研究的重点是最近发现的细胞间信号通路，脂肪通路。包括人类在内的所有动物的正常发育和生理都依赖于相对较少的高度保守的信号通路。拟议的研究将利用在果蝇中可用的强大的遗传和分子技术，该途径是在果蝇中发现的。现有证据表明，脂肪信号在果蝇中发挥着独特的作用，通过解释位置信息的梯度来调节组织生长和极性。该途径的组成部分在人类中是保守的，并在许多不同的器官系统中表达。在果蝇和人类中，一些成分已经与肿瘤的形成有关。这项提议有两个长期目标。一是更好地定义脂肪通路的生物学功能和调控，这将对理解其在正常发育和生理中的重要性具有重要意义。第二是了解这一途径在分子水平上是如何起作用的。这可能最终形成操纵通路以影响疾病状态的基础。第一个具体目标是确定脂肪调节因子的梯度如何影响脂肪活性。这些实验将为发育组织中脂肪的调节提供新的见解，并将测试我们的脂肪通路调节工作模型，该模型解释了脂肪信号如何将形态梯度与组织生长联系起来。第二个目标是确定从脂肪到疣的细胞内信号传导的分子基础。在这个目的中提出的实验将探索脂肪信号通路的“逻辑”，通过使用功能（遗传）和物理（生化）方法来探索已知脂肪通路组分之间的活性和关系。第三个目标是通过使用遗传和生化筛选来识别新的途径成分，从而增强我们对脂肪信号的理解。总之，这些实验将为理解脂肪信号传导的机制基础提供一个框架。

DESCRIPTION (provided by applicant): This research focuses on a recently identified intercellular signaling pathway, the Fat pathway. The normal development and physiology of all animals, including humans, depends upon a relatively small number of highly conserved signaling pathways. The proposed studies will take advantage of powerful genetic and molecular technologies available in Drosophila, the organism in which this pathway was discovered. Available evidence suggests that Fat signaling plays a unique role in Drosophila by interpreting gradients of positional information to regulate tissue growth and polarity. Components of the pathway are conserved in humans, and are expressed in many different organ systems. Some components have already been implicated in tumor formation, both in Drosophila and in humans. This proposal has two long range goals. One is to better define the biological functions and regulation of the Fat pathway, which will be important to understanding its importance in normal development and physiology. The second is to understand how the pathway works at a molecular level. This could ultimately form a basis for manipulating the pathway to influence disease states. The first specific aim is to determine how gradients of Fat regulators influence Fat activity. These experiments will provide new insights into the regulation of Fat in developing tissues, and will test our working model for Fat pathway regulation, which explains how Fat signaling could link morphogen gradients to tissue growth. The second aim is to define the molecular basis for intracellular signaling from Fat to Warts. The experiments proposed in this aim will explore the "logic" of the Fat signaling pathway, by using functional (genetic) and physical (biochemical) approaches to explore the activities and relationships among known Fat pathway components. The third aim is to enhance our understanding of Fat signaling by identifying new pathway components, using both genetic and biochemical screens. Together these experiments will provide a framework for understanding the mechanistic basis for Fat signaling.