Defining the mechanisms of secretion in the Drosophila salivary gland

描述(申请人提供)：许多专门的器官需要高水平的分泌活动来履行其正常的职能。例如，在免疫系统中，B细胞通过上调分泌机制分化为浆细胞，从而获得分泌大量抗体的能力，这些抗体可以对抗感染和疾病。此外，胰腺还分泌帮助食物新陈代谢的消化酶，以及调节血糖水平的激素(即胰高血糖素和胰岛素)。相应地，分泌控制的丧失被归因于许多人类疾病的发病机制，包括胰腺炎和糖尿病，以及血癌和多发性骨髓瘤。了解分泌器官发育和功能的关键之一是确定正常细胞获得分泌大量蛋白质的能力的机制。为了做到这一点，我将使用一个模型系统，果蝇唾液腺，这是这个有机体中最大的分泌器官，由专门用于高水平分泌的细胞组成。 两个唾液腺表达的转录因子(调节其他基因表达的蛋白质)Creba和XBP1在调节分泌活动方面发挥作用。已知的34个分泌途径组分基因在唾液腺中的高水平表达需要Creba。与这一发现一致的是，Creba突变体表现出分泌功能的缺陷。XBP1是一种高度保守的转录因子，参与内质网应激反应，其在哺乳动物中的对应物通常是B细胞成为分泌抗体的浆细胞所必需的。在果蝇中，XBP1在胚胎唾液腺中高度表达。因此，我认为Creba和XBP1可能协同作用，启动和维持该器官的高水平分泌功能。我的研究将确定creba和xbp1是否在相同或平行的途径上调节分泌活动，creba和xbpl突变体是否在分泌机制中存在缺陷，以及creba和/或xbp1是否直接调节制造这一机制所需基因的表达。最后，我将确定所有依赖于Creba和XBP1在唾液腺中表达的基因，潜在地揭示分泌功能所必需的其他因素。由于Creba和XBP1同源物都存在于人类中，调节果蝇唾液腺分泌活动所需的机制可能是保守的。因此，这些研究将为开发治疗以分泌功能障碍为特征的疾病的疗法提供基础。

DESCRIPTION (provided by applicant): Many specialized organs require high-level secretory activity to perform their normal functions. For example, in the immune system, B-cells differentiate into plasma cells by up-regulating the secretory machinery, thereby acquiring the ability to secrete large amounts of antibodies that fight infection and disease. Also, the pancreas secretes digestive enzymes that aid in food metabolism, as well as hormones that regulate blood glucose levels (i.e. glucagons and insulin). Correspondingly, loss of secretory control has been attributed to the pathogenesis of many human diseases, including pancreatitis and diabetes, as well as the blood cancer, multiple myeloma. One key to understanding secretory organ development and function is to define the mechanisms whereby normal cells gain the ability to secrete large amounts of protein. To do this, I will use a model system, the Drosophila salivary gland, which is the largest secretory organ in this organism and consists of cells that are specialized for high-level secretion. Two salivary gland expressed transcription factors (proteins that regulate expression of other genes) CrebA and Xbp1, have a role in regulating secretory activity. CrebA is required for the high level expression of 34 known secretory pathway component genes in the salivary gland. Consistent with this finding, CrebA mutants exhibit defects in secretory function. Xbp1 is a highly conserved transcription factor involved in ER stress response and whose mammalian counterpart is normally required for B-cells to become antibody secreting plasma cells. In Drosophila, Xbp1 is highly expressed in the embryonic salivary gland. Thus, I propose that CrebA and Xbp1 may function cooperatively to initiate and maintain the high-level secretory function of this organ. My studies will determine if CrebA and Xbp1 work in the same or parallel pathways to mediate secretory activity, if CrebA and xbpl mutants have defects in the secretory machinery, and if CrebA and/or Xbp1 directly regulate expression of the genes required to make this machinery. Finally, I will identify all of the genes that depend on CrebA and Xbp1 for their expression in the salivary gland, potentially revealing additional factors necessary for secretory function. Since both CrebA and Xbp1 homologues exist in humans, the mechanisms required to regulate secretory activity in the Drosophila salivary gland are likely to be conserved. Thus, these studies will provide a foundation for the development of therapeutics to treat diseases characterized by secretory dysfunction.