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: 6697475
• 负责人: Raul Martin Torres
• 金额: $ 34.29万
• 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/6697475
• 关键词: B cell receptor; B lymphocyte; actins; biological signal transduction; cell differentiation; chemokine; chemokine receptor; 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，对这些分子如何影响B细胞发育和免疫应答的了解相对较少。本申请的长期目标是从分子上确定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应答。这一目标部分是由我们对小鼠品系的初步分析激发的，所述小鼠品系被工程改造为缺乏调节B谱系细胞内七螺旋受体信号传导的信号传导分子。使用这些突变体与野生型，新的，和建立的小鼠模型的B细胞的发展和功能，我们测试我们的中心假设，趋化因子受体信号转导调节在体内选择新产生的B细胞和协调适当的B细胞的运动在免疫反应。我们在三个具体的目标，其中第一个检查是否趋化因子受体的反应性调节过程中B细胞的发展作为一种机制，帮助选择不成熟的B细胞。具体目标2将研究不同的趋化因子如何指导成熟的B细胞在抗原活化过程中的免疫反应的早期阶段。上述两个目标的成功实施将说明调节趋化因子应答如何影响B细胞生物学，尽管将提供对细胞内如何调节趋化因子受体信号传导的分子细节的有限了解。最终，趋化因子反应涉及受体信号传导和随后的肌动蛋白细胞骨架的重组，因为细胞通过趋化梯度迁移。具体目标3研究了趋化因子受体信号传导如何在B细胞内调节的分子性质及其与肌动蛋白细胞骨架偶联的基础。通过实现这一建议的目标，这些研究不仅将进一步了解趋化因子如何协调免疫系统的功能，但也将提高我们的基础知识的机制，导致B细胞的耐受性和有效的体液反应。