Homeostasis of the ER in Differentiating B Cells

B 细胞分化过程中 ER 的稳态

• 批准号: 7030296
• 负责人: JOSEPH W BREWER
• 金额: $ 29万
• 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/7030296
• 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。ER是膜和分泌蛋白成熟的专门隔室。因此，ER是免疫球蛋白链折叠并组装成功能性抗体的位点。当B淋巴细胞分化为分泌抗体的浆细胞时，ER扩张并适应高速率的抗体产生。因此，在分化的B细胞中调节ER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）的细胞内信号传导途径监测ER中蛋白质折叠的状态，并将该信息传递给调节ER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。ER扩增包括许多ER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。这两个事件都与XBP1（S）有关。该项目侧重于四个具体目标。首先，ER的蛋白质和脂质组成将在分化中的B细胞和成纤维细胞模型中表征，在所述成纤维细胞模型中，通过XBP 1（S）的强制表达诱导ER扩增。其次，将在这些系统中评估扩增的ER支持蛋白质生物合成的能力。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，调节雌激素受体生物发生的因素将被确定使用生物化学和遗传学的方法。这些研究将产生关于UPR调节事件的新信息，这些事件控制浆细胞发育，产生有效的抗体应答，并介导ER稳态。重要的是，UPR与许多生理学上重要的过程有关，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，许多灾难性疾病，包括溶酶体贮积病、囊性纤维化和阿尔茨海默病，都与ER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。