Regulating TGF-beta Signaling in Drosophila

描述（由申请人提供）：TGF-ss超家族是在人体中发现的最大的分泌信号分子群。它们调节了大量的细胞、发育和生理过程，包括早期轴发育、胚层规范、原肠形成、器官发生和左右不对称。我们将使用一种经过充分研究的模式生物（果蝇）来阐明TGF-ss信号通路活动在发育过程中受到调节的一般原理。在Aim 1中，我们将研究三种新的基因产物在早期胚胎中控制Dpp信号传导的机制。这些实验将显著提高我们对细胞外因子如何影响体内TGF-ss因子的信号动力学的理解。在Aim 2中，我们将结合果蝇分子遗传学和MDCK细胞的蛋白质组学来确定TGF-ss II型受体基底外侧定位在上皮细胞中的功能意义和机制。这些实验将大大提高我们对这一主要信号通路中的受体如何传递到细胞膜的不同亚室以及这如何影响组织发育的理解。在目标3中，我们将使用分子遗传学方法来确定一个亚家族（激活素）如何影响另一个亚家族（bmp）的信号输出来控制组织生长。这项工作将确定交叉TGF-ss通路信号或非规范信号是否有助于生长调节，这是许多组织发展和疾病过程中的一个重要问题。对人类健康的影响：在人类中，改变TGF-ss因子表达或调节的遗传和体细胞突变是许多疾病过程的主要因素，包括癌症、转移、纤维化、免疫调节、心血管疾病和结缔组织疾病。因此，医学界目前正在努力开发治疗干预策略，旨在在治疗各种疾病或损伤情况时操纵该途径的活动。我们的研究旨在了解这些因子的活性如何在模式生物的时间和空间上受到调节，这将有助于确定新的治疗靶点和/或开发更有效的治疗方案。

DESCRIPTION (provided by applicant): The TGF-ss superfamily is the largest group of secreted signaling molecules found in man. They regulate a very large number of cellular, developmental and physiological processes including early axial development, germ layer specification, gastrulation, organogenesis, and left right asymmetry. We will use a well-studied model organism (Drosophila) to elucidate general principles by which the activities of TGF-ss signaling pathways are regulated during development. In Aim 1 we will examine mechanisms by which three new gene products control Dpp signaling in the early embryo. These experiments will significantly improve our understanding of how extracellular factors, affect signaling dynamics of TGF-ss factors in vivo. In Aim 2 we will determine the functional significance and mechanism of TGF-ss type II receptor basolateral localization in epithelial cells using a combination of Drosophila molecular genetics and proteomics in MDCK cells. These experiments will considerably enhance our understanding of how receptors in this major signaling pathway are delivered to different sub-compartments of the cell membrane and how this affects tissue development. In Aim 3 we will use molecular genetics methods, to determine how one sub-family (Activins) influences the signaling output of another subfamily (BMPs) to control tissue growth. This work will determine whether cross TGF-ss- pathway signaling or non-canonical signaling contributes to growth regulation, an important issue in the development of many tissues and disease processes. Impact on human health: In humans, genetic and somatic mutations that alter the expression or regulation of TGF-ss factors are major contributors to numerous disease processes including cancer, metastasis, fibrosis, immune regulation, cardiovascular disease, and connective tissue disorders. Therefore, there is currently much effort within the medical community to develop therapeutic intervention strategies aimed at manipulating the activities of this pathway during treatment of various disease or injury situations. Our studies aimed at understanding how the activity of these factors is regulated in time and space in a model organism should aid in the identification of new therapeutic targets and/or development or more effective treatment protocols.