Control of B-lineage cell migration during differentiation in bone marrow

骨髓分化过程中 B 谱系细胞迁移的控制

• 批准号: 8531469
• 负责人: JOAO PEREIRA
• 金额: $ 41.52万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531469
• 关键词: Adhesions; Adhesives; Autoimmune Diseases; B-Cell Development; B-Lymphocytes; Blood; Bone Marrow; CXCR4 gene; Cell Communication; Cell Count; Cell Lineage; Cell Surface Receptors; Cells; Chemotactic Factors; Defect; Development; Discontinuous Capillary; Hematopoietic; Human; Immature B-Lymphocyte; Immigration; Immune System Diseases; Immune system; Immunoglobulin Genes; Immunologic Deficiency Syndromes; Individual; Integrins; Interleukin 7 Receptor; Interleukin-7; Laboratories; Ligands; Light; Lipids; Lymphocyte; Lymphoid; Lymphopenia; Mediating; Mesenchymal; Microanatomy; Microscope; Microscopy; Modeling; Molecular; Movement; Mus; Organ; Photons; Positioning Attribute; Process; Proteins; Protocols documentation; Role; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptor; Staging; Stromal Cells; Systems Development; Testing; Vaccine Design; Work; cell motility; cell type; cytokine; in vivo; insight; intravital microscopy; migration; multi-photon; novel therapeutics; pathogen; progenitor; receptor; receptor coupling; research study; sphingosine 1-phosphate; trafficking

DESCRIPTION (provided by applicant): The quest for understanding lymphocyte migration has challenged multiple laboratories for several decades now. The recent development of multi-photon microscopes is beginning to shed some light on the dynamics of lymphocyte movement in secondary lymphoid organs. In contrast, there is still an almost complete lack of information on B-lineage cell migration and positioning during differentiation in bone marrow (BM). B-cell precursors interact with specialized BM stromal cells expressing critical signals, such as IL-7. IL 7 is essential for maintaining B-lineage specification and differentiation. Yet, the mechanism, and the dynamics, of early B cell precursor interaction with IL-7+ cells remain uncharacterized. In specific aim 1, we define a strategy for visualizing B cell precursor interactions with IL-7+ stromal cells by intravital multiphoton microscopy. Moreover, we will test the hypothesis that defects in B cell precursor migration and adhesion to IL-7+ cells cripple B cell development and cause of B-lymphopenia. We have previously described movement of developing B cells in BM parenchyma and sinusoids. The mechanism(s) controlling B cell precursor motility in BM remain uncharacterized. In specific aim 2 we propose to characterize the mechanism of B cell precursor migration in BM. In late stages of B cell development, immature B-lymphocytes acquire egress capability and exit BM through the sinusoidal network. A significant body of work has demonstrated that the signaling lipid sphingosine-1-phosphate (S1P), and S1P receptors are critical for lymphocyte egress from primary and secondary lymphoid organs. However, we were, recently, surprised to find a minimal role for S1P and its G?i protein coupled receptor S1P1 in immature B cell egress from BM. In an attempt to further define S1P-independent egress mechanism(s), we propose in specific aim 3 to assess if alternative G?i protein coupled receptor(s) are involved in this process. Finally, we will devise a strategy for visualizing immature B cell egress from BM into sinusoids. Combined these studies will begin to detail a model of the microanatomy of B cell development.

描述（由申请人提供）：几十年来，寻求理解淋巴细胞迁移已挑战了多个实验室。多光子显微镜的最新发展开始阐明继发性淋巴机构中淋巴细胞运动的动力学。相反，在骨髓（BM）分化过程中，几乎完全缺乏有关B-Linege细胞迁移和定位的信息。 B细胞前体与表达关键信号的专门BM基质细胞相互作用，例如IL-7。 il 7对于维持B-Linege规范和分化至关重要。然而，早期B细胞前体与IL-7+细胞相互作用的机理和动力学仍然没有表征。在特定的目标1中，我们定义了通过插入式多光子显微镜与IL-7+基质细胞可视化B细胞前体相互作用的策略。此外，我们将检验以下假设：B细胞前体迁移和对IL-7+细胞的粘附粘在B细胞的发育和B-淋巴细胞减少症的原因。我们先前已经描述了BM类细胞肌和正弦体中B细胞发育的运动的运动。 BM中控制B细胞前体运动的机制仍然没有表征。在特定目标2中，我们建议表征BM细胞前体迁移的机理。在B细胞发育的后期，未成熟的B淋巴细胞可通过正弦网络获得出口能力并退出BM。一项重要的工作表明，信号脂质鞘氨醇1-磷酸（S1P），而S1P受体对于来自原发性和继发性淋巴机器人的淋巴细胞出口至关重要。但是，最近，我们惊讶地发现S1P及其G？i蛋白偶联受体S1P1在BM中的未成熟B细胞出口中的作用最小。为了进一步定义独立于S1P的出口机制，我们建议在特定目标3中评估此过程是否涉及替代的G？i蛋白偶联受体。最后，我们将制定一种可视化不成熟的B细胞从BM出口到正弦体的策略。这些研究的结合将开始详细介绍B细胞发育的微解剖学模型。