Regulation of B Lymphocyte Proliferation by Antigen

抗原对 B 淋巴细胞增殖的调节

• 批准号: 7535203
• 负责人: Anthony L Defranco
• 金额: $ 36.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-01-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535203
• 关键词: Actins; Antigen Receptors; Antigens; B-Cell Activation; B-Cell Development; B-Lymphocytes; Biological; Cell Line; Cell membrane; Cell physiology; Cell surface; Cells; Cholesterol; Complex; Cytoskeleton; Development; Discrimination; Event; Family; Glycolipids; Goals; Guanosine Triphosphate Phosphohydrolases; Image; Immune system; Infectious Agent; Language; Lipids; Lymphocyte; Mature B-Lymphocyte; Mediating; Membrane; Membrane Microdomains; Molecular; Motor; Movement; Muscle; Myosin ATPase; NF-kappa B; Pathway interactions; Phenotype; Play; Process; Property; Protein Isoforms; Proteins; Receptor Signaling; Receptors, Antigen, B-Cell; Recruitment Activity; Regulation; Relative (related person); Role; Signal Pathway; Signal Transduction; Signaling Molecule; Sphingolipids; Staging; Structure; Testing; Work; ezrin; in vivo; lymphocyte proliferation; moesin; novel; physical state; rac1 GTP-Binding Protein; rho; scaffold; src-Family Kinases

The fate of B cells is highly dependent on signals from the B cell antigen receptor (BCR) for development, tolerance, and activation decisions. The overall goal of this project is to understand the role of cholesterol- rich subdomains of the plasma membrane called lipid rafts in BCR signal transduction. Recent work in B cells has established that lipid rafts play a role in BCR signaling. Lipid rafts exist primarily as small, highly dynamic structures that coalesce into larger and more stable lipid rafts upon cell stimulation. BCR stimulation leads to its movement from the non-lipid raft plasma membrane into lipid rafts and induces coalescence of lipid rafts, eventually leading to a large lipid raft patch or cap on the cell surface. In Specific Aim 1, the mechanism of BCR-induced lipid raft coalescence will be studied. BCR stimulation causes ezrin to become dephosphorylated and to release its connection between some lipid raft proteins and the actin cytoskeleton. We shall test if this release promotes lipid raft coalescence and BCR signaling. We hypothesize that the later stages of lipid raft coalescence require active processes involving myosins and will attempt to identify the myosin isoform responsible. BCR stimulation also leads to outgrowth of long filopdia- like projections ("cytonemes") and in Specific Aim 2, we shall determine the mechanism of outgrowth of these projections. We shall explore the role of the B144 protein, the Rac1 and Cdc42 GTPases, and myosin 10 and its close relatives. In Specific Aim 3, we shall examine the connection of lipid rafts to the ability of the BCR to activate the key transcription factor, NF-kB. Carmal, a key scaffold molecule for this signaling pathway, is localized to lipid rafts and it recruits other components of this pathway to lipid rafts following BCR stimulation. The importance of Carmal localization to lipid rafts and of lipid raft coalescence for activation of NF-kB will be determined. Finally, in Specific Aim 4, we shall examine lipid raft coalescence and NF-kB pathway activation in immature B cells and B cell lines' of immature phenotype, which appear to differ from mature B cells in these processes. . Lay Language Statement: The ability of the immune system to respond to infectious agents depends on the function of the antigen receptors of lymphocytes. This function appears to involve changes in a subdomain of the plasma membrane called lipid rafts and the mechanisms of these changes will be studied.

B细胞的命运高度依赖于B细胞抗原受体（BCR）的信号进行发育， 公差和激活决策。该项目的总体目标是了解胆固醇的作用 BCR信号转导中称为脂质筏的质膜的丰富亚域。 B的最新工作 细胞已经确定脂质筏在BCR信号传导中起作用。脂质筏主要存在很小，高度存在 细胞刺激后，将融合成更大，更稳定的脂质筏的动态结构。 BCR 刺激导致其从非脂筏质膜运动到脂质筏并诱导 脂质筏的结合，最终导致细胞表面上的脂质筏斑块或盖。具体 AIM 1，将研究BCR诱导的脂质筏结合的机制。 BCR刺激会导致Ezrin 成为去磷酸化并释放其在某些脂质筏蛋白和肌动蛋白之间的连接 细胞骨架。我们将测试该版本是否促进了脂质筏结合和BCR信号传导。我们 假设脂质筏结合的后期阶段需要涉及肌球蛋白的活动过程，并将 尝试识别负责的肌球蛋白同工型。 BCR刺激还会导致长丝藻的产物 像预测（“细胞质”）和特定目标2一样，我们将确定生长的机理 这些预测。我们将探讨B144蛋白，Rac1和Cdc42 GTPases和肌球蛋白的作用 10及其近亲。在特定的目标3中，我们将研究脂质筏与能力的联系 BCR激活关键转录因子NF-KB。 Carmal，用于此信号的钥匙支架分子 途径位于脂质筏上，并在BCR后募集该途径的其他组成部分 刺激。 Carmal定位对脂质筏的重要性和脂质筏合并的重要性 NF-KB将被确定。最后，在特定的目标4中，我们将检查脂质筏结合和NF-KB 未成熟的B细胞和未成熟表型的B细胞系中的途径激活，这似乎与 在这些过程中成熟的B细胞。 。 外行语言陈述：免疫系统对传染剂的反应能力取决于 淋巴细胞抗原受体的功能。此功能似乎涉及子域中的更改 将研究称为脂质筏的质膜和这些变化的机制。