Homeostasis of the ER in Differentiating B Cells

B 细胞分化过程中 ER 的稳态

• 批准号: 6920087
• 负责人: JOSEPH W BREWER
• 金额: $ 29.7万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6920087
• 关键词: B lymphocyte; biological signal transduction; cell differentiation; cell growth regulation; endoplasmic reticulum; genetically modified animals; homeostasis; laboratory mouse; leukocyte activation /transformation; molecular chaperones; protein folding

DESCRIPTION (provided by applicant): The long-term goal of this research program is to delineate the molecular mechanisms that regulate homeostasis of the endoplasmic reticulum (ER) in B-lymphocytes. The ER is a specialized compartment for the maturation of membrane and secreted proteins. As such, the ER is the site where immunoglobulin chains fold and assemble into functional antibodies. When B-lymphocytes differentiate into antibody-secreting plasma cells, the ER expands and adapts to accommodate high-rate antibody production. Therefore, the mechanisms that regulate ER homeostasis in differentiating B cells are critical for antibody-mediated immunity. An intracellular signaling pathway, termed the unfolded protein response (UPR), monitors the status of protein folding in the ER and transmits that information to mechanisms that modulate the ER environment. A key UPR transcriptional activator, XBP1(S), is required for plasma cell development. ER expansion includes increased expression of many ER resident proteins and elevated synthesis of phospholipids necessary for membrane biosynthesis. Both of these events have been linked to XBP1(S). This project focuses on four specific aims. First, the protein and lipid composition of the ER will be characterized in differentiating B cells and in a fibroblast model in which ER expansion is induced by enforced expression of XBP1(S). Second, the ability of the expanded ER to support protein biosynthesis will be evaluated in these systems. Third, the mechanism by which phospholipid biosynthesis increases during ER expansion will be investigated. Finally, factors that regulate ER biogenesis will be identified using biochemical and genetic approaches. These studies will yield new information concerning UPR-regulated events that control plasma cell development, generate efficient antibody responses, and mediate ER homeostasis. Importantly, the UPR has been linked to a number of physiologically significant processes including pancreatic function, skeletal development, oxidative stress, and macrophage apoptosis in atherosclerotic lesions. In addition, a number of catastrophic disorders including lysosomal storage diseases, cystic fibrosis, and Alzheimer disease have been linked to protein maturation errors in the ER. A mechanistic understanding of ER homeostasis might lead to the development of novel therapeutics for these diseases.

描述（由申请人提供）：本研究计划的长期目标是描述调节b淋巴细胞内质网（ER）稳态的分子机制。内质网是膜和分泌蛋白成熟的专门隔间。因此，内质网是免疫球蛋白链折叠并组装成功能性抗体的部位。当b淋巴细胞分化为分泌抗体的浆细胞时，内质网扩大并适应高速率抗体的产生。因此，在B细胞分化过程中调节内质网稳态的机制对于抗体介导的免疫至关重要。一种称为未折叠蛋白反应（UPR）的细胞内信号通路监测内质网中蛋白质折叠的状态，并将该信息传递给调节内质网环境的机制。一个关键的UPR转录激活因子XBP1(S)是浆细胞发育所必需的。内质网扩增包括许多内质网驻留蛋白的表达增加和膜生物合成所必需的磷脂合成升高。这两种事件都与XBP1(S)有关。该项目侧重于四个具体目标。首先，内质网的蛋白质和脂质组成将在分化的B细胞和成纤维细胞模型中被表征，在这种模型中，内质网的扩增是由XBP1的强制表达诱导的(S)。其次，扩大内质网支持蛋白质生物合成的能力将在这些系统中进行评估。第三，研究内质网扩张过程中磷脂生物合成增加的机制。最后，调节内质网生物发生的因素将使用生化和遗传方法确定。这些研究将产生关于upr调控事件的新信息，这些事件控制浆细胞发育，产生有效的抗体反应，并介导内质网稳态。重要的是，UPR与许多重要的生理过程有关，包括胰腺功能、骨骼发育、氧化应激和动脉粥样硬化病变中的巨噬细胞凋亡。此外，包括溶酶体贮积病、囊性纤维化和阿尔茨海默病在内的许多灾难性疾病都与内质网中的蛋白质成熟错误有关。对内质网稳态的机制理解可能会导致这些疾病的新疗法的发展。