Systems approach to identify phosphoregulators of mouse lung development

描述（由申请人提供）：了解组织和器官形成的主要目标是将关键发育信号与负责指导和控制这些发育的基本分子途径联系起来。基因组时代创造了一个巨大的知识体系，并提供了细胞分子调控的全球概况。然而，在理解这些调节因子的功能方面存在相当大的差距，在理解这些调节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更大的差距。当前最先进的技术需要一种全面的方法或系统的方法，在这种方法中，必须解决途径之间的相互作用和不同途径汇合所产生的复杂性，以进一步了解与人类健康和疾病相关的关键器官的发展。该研究项目旨在通过全面了解激酶/磷酸酶调节的分子途径及其在组织小鼠胚胎肺形成中的作用之间的功能关系来填补这一空白。本提案利用各种已建立的以及新的和创新的细胞生物学和发育技术来追求以下目标。目的1将结合功能基因组学（功能丧失）筛选和肺外植体培养的形态学分析，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kinome/phosphatome分子途径调节因子与我们的功能丧失筛选结果相关联。在2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。长期目标是为治疗包括肺癌、肺气肿、哮喘和早产儿未成熟肺在内的人类疾病提供潜在靶点。项目的叙述。总体目标是使用一种全面系统的方法来提供对胚胎肺发育的基本分子调节因子的基本理解。这些发现有可能为早产儿未成熟肺的治疗以及包括肺癌、肺气肿和哮喘在内的人类疾病提供新的靶点。

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.