Chemokine response in B cell development and function

B 细胞发育和功能中的趋化因子反应

• 批准号: 6843138
• 负责人: Raul Martin Torres
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6843138
• 关键词: B cell receptor; B lymphocyte; actins; biological signal transduction; cell differentiation; chemokine; cytokine receptors; genetically modified animals; laboratory mouse; receptor coupling

DESCRIPTION (provided by the applicant): Chemokines and their receptors have emerged as important mediators of hematopoietic cell development, homeostasis, and function. However, relatively little is understood about how these molecules influence B cell development and immune response. The long-term goal of this application is to molecularly define how chemokines and their receptors participate in the selection of B cells and their response to foreign antigens as mature lymphocytes. This objective has been partially motivated by our preliminary analyses of a mouse line engineered to be deficient for a signaling molecule that regulates heptahelical receptor signaling within B lineage cells. Using these mutants in combination with wild-type, novel, and established mouse models of B cell development and function we test our central hypothesis that chemokine receptor signaling is regulated in vivo for selecting newly-generated B cells and orchestrating appropriate B cell movements during an immune response. We address this hypothesis in three specific aims the first of which examines whether chemokine receptor responsiveness is regulated during B cell development as a mechanism that aids in the selection of immature B cells. Specific Aim 2 will investigate how distinct chemokines guide mature B cells upon antigen activation during the early phase of an immune response. Successful execution of the above two Aims will illustrate how regulating chemokine responses may influence B cell biology although will provide limited insight into the molecular details of how chemokine receptor signaling is regulated within the cell. Ultimately, chemokine responses involve receptor signaling and subsequent reorganization of the actin cytoskeleton as cells migrate through a chemoattractant gradient. Specific Aim 3 investigates the molecular nature of how chemokine receptor signaling is regulated within B cells and the basis of its coupling to the actin cytoskeleton. By accomplishing the goals of this proposal, these studies will not only further our understanding of how chemokines orchestrate immune system function, but will also enhance our basic knowledge on the mechanisms leading to B cell tolerance and effective humoral responses.

描述（由申请人提供）：趋化因子及其受体已成为造血细胞发育、稳态和功能的重要介质。然而，人们对这些分子如何影响 B 细胞发育和免疫反应的了解相对较少。该应用的长期目标是从分子水平上定义趋化因子及其受体如何参与 B 细胞的选择及其作为成熟淋巴细胞对外来抗原的反应。这一目标部分源于我们对小鼠品系的初步分析，该小鼠品系被设计为缺乏调节 B 谱系细胞内七螺旋受体信号传导的信号分子。使用这些突变体与野生型、新型和已建立的 B 细胞发育和功能小鼠模型相结合，我们测试了我们的中心假设，即趋化因子受体信号在体内受到调节，以选择新生成的 B 细胞并在免疫反应。我们通过三个具体目标来解决这一假设，第一个目标是检查趋化因子受体反应性是否在 B 细胞发育过程中受到调节，作为一种有助于选择未成熟 B 细胞的机制。具体目标 2 将研究不同的趋化因子如何在免疫反应早期阶段抗原激活时引导成熟 B 细胞。上述两个目标的成功执行将说明调节趋化因子反应如何影响 B 细胞生物学，尽管对细胞内趋化因子受体信号传导如何调节的分子细节提供有限的了解。最终，趋化因子反应涉及受体信号传导以及随后当细胞通过趋化剂梯度迁移时肌动蛋白细胞骨架的重组。具体目标 3 研究 B 细胞内趋化因子受体信号传导如何调节的分子性质及其与肌动蛋白细胞骨架偶联的基础。通过实现该提案的目标，这些研究不仅将进一步加深我们对趋化因子如何协调免疫系统功能的理解，还将增强我们对导致 B 细胞耐受和有效体液反应机制的基础知识。