Regulation of Organ Size and Shape by Fat Signaling

项目摘要/摘要 发育过程中生长和形态发生的协调对正常器官的形成至关重要 形状和大小以及不适当的大小和形状的器官通常会导致器官功能障碍和先天性 反常现象。原钙粘附素、纤维粘附素和脂肪构成了高度保守的信号通路， 通过调节平面细胞极性对河马信号和形态发生的影响来调节生长 和定向细胞分裂。一如既往，影响这一途径的突变会导致许多疾病。 影响器官形状或大小的。对果蝇的研究为了解这种分子提供了重要的见解 通过脂肪信号调节器官大小和形状的机制。最近我发现了一种新基因 Vamana，它是脂肪信号通路的关键下游成分。另外，我最近的工作 已经确定了这一途径的几个新的调节因子，并导致了有趣的发现，表明 囊泡运输在调节脂肪信号方面起着至关重要的作用，这一方面的研究很少。在AIM 1、我建议研究组织这一信号通路的囊泡运输机制。 具体地说，我将研究泛素化和棕榈酰化在这一成分的贩运中的相互作用 路径。从飞行员的基因筛查中，我最近分离出了一种新的突变，大圆翼(BRW)，它 显示脂肪信号通路突变的表型特征。在目标2中，我将描述BRW如何， 调节这一途径。最后，基于试点筛选的成功，我建议确定其他 脂肪信号调节器通过创新的正向增益屏功能。虽然我最近的工作使 为了产生这些有趣的发现和研究计划，我的直接目标是获得更多 实况成像、囊泡运输、泛素化和棕榈酰化方面的培训，这是进一步 开发这些项目。我已经安排了一批杰出的导师，他们将为我提供这方面的帮助 额外的培训。在该奖项的指导阶段，我将与Barth Grant博士一起培训，学习如何 处理和解决泡囊贩运中的问题。我的导师肯尼斯·欧文博士将提供现场培训 Marc Gartenberg博士将为基于酵母的检测方法的开发提供指导，以识别 棕榈酰转移酶的底物。建议的培训结合我以前的研究经验 将使我能够采取多管齐下的综合方法来解开新的分子机制 调节脂肪信号。这一研究计划也将为先天性心脏病的发病机制提供洞察力。 脂肪信号中断引起的发育缺陷。独立之路奖将 使我能够获得实现眼前研究目标所需的培训和资源。此外， 建议的培训和它支持的创新研究计划将帮助我实现我的短期目标 在一所主要的大学或研究机构获得教职。这一奖项将进一步帮助我继续 我的长期目标是了解器官在发育过程中的大小和形状的调节。

Project Summary/ Abstract Coordination of growth and morphogenesis during development is critical for formation of organs of proper shape and size and improperly sized and shaped organs often lead to organ malfunction and congenital anomalies. The protocadherins, Dachsous (Ds) and Fat constitute a highly conserved signaling pathway that regulates growth through its influence on Hippo signaling and morphogenesis by regulating planar cell polarity and oriented cell divisions. Consistently, mutations affecting this pathway result in a number of diseases affecting organ shape or size. Studies in Drosophila have provided important insights into the molecular mechanisms that regulate organ size and shape by Fat signaling. Recently I have identified a new gene Vamana, which is a critical downstream component of the Fat signaling pathway. Additionally, my recent work has identified several novel regulators of this pathway and has led to intriguing findings that suggest that vesicular trafficking plays a crucial role in regulating Fat signaling, an aspect that is very little explored. In Aim 1, I propose to investigate the vesicular trafficking mechanisms that organize this signaling pathway. Specifically, I will study the interplay of ubiquitination and palmitoylation in trafficking of the components of this pathway. From a pilot genetic screen, I have recently isolated a novel mutation, Big round wings (Brw), which displays phenotypes characteristic of mutations in Fat-signaling pathway. In Aim 2, I will characterize how Brw, regulates this pathway. Finally, based on the success of the pilot screen, I propose to identify additional regulators of Fat signaling by an innovative forward gain of function screen. While my recent work has enabled me to generate these intriguing findings and the research plan, my immediate goals are to obtain additional training in live imaging, vesicular trafficking, ubiquitination and palmitoylation that are necessary to further develop these projects. I have arranged a group of distinguished mentors, who will provide me with this additional training. During the mentored phase of this award, I will train with Dr. Barth Grant to learn how to approach and solve problems in vesicular trafficking. My mentor, Dr. Kenneth Irvine will provide training in live imaging, and Dr. Marc Gartenberg will provide mentorship on development of the yeast based assay to identify substrates of palmitoyl transferases. The proposed training combined with my previous research experience will enable me to undertake a multipronged comprehensive approach to unravel novel molecular mechanisms regulating Fat signaling. This research plan will also provide insight into pathogenesis of congenital developmental defects arising from disruptions in Fat signaling. The pathway to independence award will enable me to acquire the training and resources I need to achieve my immediate research goals. Further, the proposed training and the innovative research program it supports will help me achieve my short-term goal of obtaining a faculty position at a major university or research institution. The award will further assist me pursue my long-term goal of understanding regulation of organ size and shape during development.