Systems approach to identify phosphoregulators of mouse lung development

描述(由申请人提供)：理解组织和器官形成的一个主要目标是将关键的发育信号与负责指导和控制这种发育的基本分子途径联系起来。基因组时代创造了大量的知识，并提供了细胞分子调控的全球概览。然而，在了解这些调控因子的功能方面存在着相当大的差距，在理解这些调控因子与它们产生复杂三维组织的机制之间的联系方面存在着更大的差距。目前的最新水平需要一种全面的方法或系统的方法，其中必须解决途径之间的相互作用和不同途径汇聚所造成的复杂性，以促进我们对与人类健康和疾病相关的关键器官发育的理解。这项拟议的研究项目旨在通过全面了解激酶/磷酸酶调节的分子通路之间的功能关系以及它们在组织小鼠胚胎肺形成中的作用来填补这一空白。这项提议利用各种既有的以及新的和创新的细胞生物学和发展技术来实现以下目标。目的1利用功能基因组学(功能丧失)筛查和肺外植体培养的形态分析相结合的方法，确定参与胚胎肺形态发生的激酶和磷酸酶。目的2将定义参与肺形态发生的分子途径，将已知的动态组/磷酸组之间的分子途径调节因子与我们的功能丧失筛查中的命中结果相关联。在两年内，我们的方法将导致对肺形态发生是如何由磷调节蛋白和关键发育信号之间的串扰控制的基本理解。一个长期目标是为人类疾病的治疗提供潜在的靶点，包括肺癌、肺气肿、哮喘和早产儿的未成熟肺。项目叙事。总体目标是使用一种全面的系统方法来提供对胚胎肺发育的基本分子调节的基本了解。这些发现有可能为治疗早产儿的未成熟肺以及包括肺癌、肺气肿和哮喘在内的人类疾病提供可能的新靶点。

DESCRIPTION (provided by applicant): A major goal in understanding tissue and organ formation is to link key developmental signals to the fundamental molecular pathways responsible for guiding and controlling such development. The genomic era has created a tremendous body of knowledge and provided a global overview of the molecular regulators of the cell. However, there is a considerable gap in understanding the function of these regulators and even wider gap in understanding the links between these regulators and the mechanisms by which they generate complex three-dimensional tissues. The current state-of-the-art requires a comprehensive approach or systems approach in which the interaction between pathways and the complexity created by the convergence of different pathways must be addressed to further our understanding of the development of key organs relevant to human health and disease. The proposed research project aims at filling this gap by generating a comprehensive understanding of the functional relationship between kinase/phosphatase regulated molecular pathways and their roles in organizing the formation of the embryonic mouse lung. This proposal utilizes a variety of established as well as new and innovative cell biological and developmental techniques to pursue the following aims. Aim 1 will define the kinases and phosphatases involved in embryonic lung morphogenesis using a combination of a functional genomics (loss of function) screen with morphological analysis in lung explant cultures. Aim 2 will define the molecular pathways involved in lung morphogenesis, correlating known molecular pathway regulators among the kinome/phosphatome with hits from our loss of function screen. Within 2 years our approach will lead to a fundamental understanding of how lung morphogenesis is controlled by phosphoregulatory proteins and the cross-talk between key developmental signals. A long term goal is to provide potential targets for the treatment of human diseases including lung cancer, emphysema, asthma, and the immature lungs of premature infants. PROJECT NARRATIVE. The overall goal is to use a comprehensive systematic approach to provide a fundamental understanding of the essential molecular regulators of embryonic lung development. These findings have the potential to provide possible new targets for the treatment of the immature lungs of premature infants and of human diseases including lung cancer, emphysema, and asthma.