Drosophila salivary gland, a model for studying the molecular basis of secretion

描述(申请人提供)：分泌过程发生在所有细胞中，从大多数细胞特有的非常低的水平，到专门分泌的器官中发现的极高水平。这项建议的目标是确定驱动分泌能力的转录机制，并确定专门化分泌器官(包括胰腺、颌下腺和乳腺)的发育和功能所需的新基因。从以前的工作中我们知道bZip转录因子Creba是分泌的主要调节因子，然而，我们的数据表明，分泌能力的上调需要额外的转录因子作用于Creba下游。微阵列分析确定了16个依赖于Creba正常表达的转录因子。在该奖项的指导阶段，研究将集中在其中之一的特征，都铎-SN。本研究的第一个目的是确定Tudor-SN在分泌器官发育中的作用，并确定Tudor-SN对分泌能力的作用机制。微阵列筛选还发现了100多个新的/新的基因，这些基因以前没有涉及到分泌功能，并且具有人类同源物，其中19个已经证明在唾液腺中表达。该项目的独立阶段将使用果蝇唾液腺系统和人类分泌细胞来识别和表征在分泌途径中具有新作用的基因。我们知道Creba在人类中高度保守，它的同系物Creb3L1和Creb3L2在分泌活动中也有重要作用。因此，我们使用果蝇唾液腺的研究将使我们能够识别在人类分泌器官的发育和功能中具有重要作用的基因。这个职业发展奖的最终目标是建立果蝇唾液腺作为研究分泌器官如何发展分泌能力的模式系统，同时建立一个有竞争力的研究计划，为我建立自己的实验室提供良好的基础。 公共卫生相关性：许多人类疾病是由分泌功能障碍引起的，包括糖尿病、胰腺炎、干燥综合征和多发性骨髓瘤。了解分泌器官如何发展分泌正常功能所需的大量蛋白质的能力，对于开发治疗这些疾病的新治疗策略至关重要。

DESCRIPTION (provided by applicant): The process of secretion happens in all cells, from the very low levels characteristic of most cells, to the extremely high levels found in organs specialized for secretion. The goal of this proposal is to determine the transcriptional mechanisms that drive secretory capacity and to identify novel genes required for the development and function of the specialized secretory organs, including the pancreas, submandibular and mammary glands. We know from previous work that the bZip transcription factor, CrebA, is the major regulator of secretion, however, our data suggests that upregulation of secretory capacity requires additional transcription factors that act downstream of CrebA. Microarray analysis identified 16 transcription factors that depend on CrebA for normal expression. During the mentored phase of the award, research will focus on the characterization of one of these, Tudor-SN. The first aim of this proposal will characterize the role of Tudor-SN in secretory organ development, and determine the mechanism of Tudor-SN function on secretory capacity. The microarray screen also identified over 100 new/novel genes that have not been previously implicated in secretory function and that have human homologues, of which nineteen have documented expression in the salivary gland. The independent phase of this project will use both the Drosophila salivary gland system and human secretory cells to identify and characterize genes with novel roles in the secretory pathway. We know that CrebA is highly conserved in humans, and that its homologues, Creb3L1 and Creb3L2 also have important roles in secretory activity. Thus our studies using the Drosophila salivary gland will allow us to identify genes with important roles in the development and function of secretory organs in humans. The ultimate goal of this career development award is to establish the Drosophila salivary gland as a model system for studying how secretory organs develop secretory capacity, while at the same time building a competitive research program that will provide a good foundation for when I set up my own laboratory. PUBLIC HEALTH RELEVANCE: Many human diseases result from secretory dysfunction, including diabetes, pancreatitis, Sj"gren's syndrome and multiple myeloma. Understanding how secretory organs develop the capacity to secrete the large amounts of protein required for normal function is essential to developing new therapeutic strategies to treat these diseases.