Early Events in Mammalian B-Cell Differentiation

哺乳动物 B 细胞分化的早期事件

• 批准号: 7925000
• 负责人: Paul Wayne Kincade
• 金额: $ 29.34万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925000
• 关键词: Antibodies; Antibody Formation; Autoimmune Diseases; B cell differentiation; B-Lymphocytes; Biological Assay; Blood Cells; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Adhesion Molecules; Cell Culture Techniques; Cell Lineage; Cell Separation; Cells; Chronic; Complex; Computer Systems Development; Confusion; Consensus; Cues; Data; Dedications; Dendritic Cells; Disease; Drug Prescriptions; Event; Flow Cytometry; Goals; Healed; Hematopoietic; Hematopoietic stem cells; Hormones; Human; Immune system; Individual; Infection; Knock-in Mouse; Laboratories; Learning; Life; Ligands; Lymphocyte; Lymphoid; Lymphopoiesis; Modeling; Mus; Myelogenous; Outcome; Patients; Physiological; Population; Positioning Attribute; Process; Production; Receptor Signaling; Recovery; Reporter; Retinoids; Running; Series; Simplexvirus; Speed; Staging; Stem cells; Study models; Techniques; Textbooks; Tissues; Toll-like receptors; Transplantation; Tretinoin; Viral; Virus; Virus Diseases; abstracting; cancer therapy; cell type; cellular targeting; chemotherapy; clinical application; cytokine; healing; improved; interest; microbial; novel therapeutics; pathogen; progenitor; programs; research study; response; stem; success

DESCRIPTION (provided by applicant): Project Summary/Abstract Extraordinary advances are being made in our understanding of the immune system, with discovery of functionally specialized cell types. However, new data are beginning to reveal that the process by which hematopoietic stem cells (HSC) develop is more complex and less rigidly controlled than generally believed. Textbooks have long depicted simple relationships between HSC and B lymphocytes, but it now appears that there is not just one branch point where progenitors lose the option of becoming B cells and are directed to other fates. Rather, dedication and firm commitment to the B lineage is a gradual process and can be dramatically altered in response to environmental cues. There is still much to learn about endogenous cues such as those provided by cytokines, hormones and cell adhesion molecules. In addition, we have new observations suggesting that retinoids can accelerate the process of lymphocyte formation and their effects on the bone marrow merit further study. For example, these widely prescribed drugs hold promise as agents for boosting recovery of the immune system. We are combining special knock-in mice with cell sorting, cell culture and transplantation techniques to systematically investigate these and other questions. Our lab discovered that Toll-like receptors (TLR) are expressed on hematopoietic cells, allowing these cells to recognize bacterial/viral products and several important outcomes of this interaction have already been identified. For example, TLR ligands stimulate stem cells to enter cycle and begin differentiating, while myeloid restricted cells complete their maturation. The ligands arrest B cell production and cause lymphocyte progenitors to generate several types of dendritic cells. While these new mechanisms may have survival value, we believe there are also circumstances where stem and progenitor cells need to be protected from such substances. Our lab is using defined culture conditions to study mechanisms associated with an apparent re-programming of lymphoid progenitors. In addition, we are tracking the same phenomena in HSV infected mice. Project Narrative: Our bone marrow must constantly make new blood cells, including cells responsible for antibody formation and defense against infections. Patients are vulnerable to infections following chemotherapy or transplantation, but our data suggest that it may be possible to accelerate recovery of the immune system. Basic understanding of early stages of immune system development may point the way to improved healing of damaged tissues as well as better treatments for cancer and autoimmune diseases.

项目概述/摘要随着功能特化细胞类型的发现，我们对免疫系统的理解正在取得非凡的进展。然而，新的数据开始揭示造血干细胞（HSC）发育的过程比通常认为的更复杂，更不严格控制。长期以来，教科书一直描述HSC和B淋巴细胞之间的简单关系，但现在看来，不仅仅存在一个分支点，在这个分支点上，祖细胞失去了成为B细胞的选择，并被导向其他命运。相反，对B谱系的奉献和坚定的承诺是一个渐进的过程，并且可以根据环境线索发生显著变化。关于内源性线索，如细胞因子、激素和细胞粘附分子提供的线索，还有很多需要了解的。此外，我们有新的观察结果表明，类维甲酸可以加速淋巴细胞的形成过程，其对骨髓的影响值得进一步研究。例如，这些广泛开处方的药物有望促进免疫系统的恢复。我们正在将特殊敲入小鼠与细胞分选、细胞培养和移植技术相结合，系统地研究这些问题和其他问题。