Regulation of B Cell Development by Neuropeptides

这个项目的目标是了解神经系统如何影响骨髓中新B细胞的产生。B细胞在接种疫苗或接触病原体后产生抗体。免疫系统的功能要求以受控的速度产生新的白细胞(白细胞)，包括B细胞。白细胞产生不足或过多可能导致抗击传染病、白血病、自身免疫或其他疾病状态的能力降低。因此，至关重要的是，白纹伊蚊的生产率必须维持在一定水平，以确保有足够的数量发挥其被禁的保护功能，而不会有生产过剩的风险。本项目的重点是神经肽降钙素基因相关肽(CGRP)在调节早期B细胞分化中的作用。免疫系统中的细胞具有CGRP受体，CGRP影响成熟淋巴细胞、巨噬细胞和粒细胞的活动。CGRP和另一种感觉神经肽，P物质，在调节不同白细胞群的分化中发挥作用。CGRP存在于骨髓的神经末梢，造血细胞具有CGRP受体，CGRP诱导B细胞调节性细胞因子的产生，抑制B细胞祖细胞对IL-7的反应。本项目的具体目的是证明给予CGRP可减少B细胞前体细胞的数量，鉴定B细胞系中表达CGRP受体的细胞，研究CGRP如何影响B细胞早期发育的特定阶段，并研究CGRP阻止B细胞分化的细胞机制。体内研究将确定CGRP治疗后Pre-B CFU的数量。表达CGRP受体的细胞群将通过CGRP受体的mRNA分析和对CGRP的功能反应来鉴定。降钙素基因相关肽在B细胞分化中的作用将通过对来自骨髓的细胞进行短期体外研究来研究。这些研究将检验CGRP对骨髓中存在的不同B细胞前体群体的增殖和分化的影响。初步研究表明，CGRP通过与IL-7和NFkappa-B激活有关的细胞机制抑制早期B细胞分化。研究将确定CGRP如何抑制前B细胞系中NFkappa-B的激活，并将研究CGRP如何抑制正常B细胞前体细胞中的IL-7反应。更好地了解CGRP在B细胞发育中的作用可能为新的治疗方法提供新的途径。

The objective of this project is to understand how the nervous system influences the production of new B cells in the bone marrow. B cells produce antibodies following vaccination or exposure to a pathogen. The function of the immune system requires that new white blood cells (leukocytes), including B cells, be produced at controlled rates. Under or overproduction of leukocytes could lead to a reduced capacity to fight infectious disease or to leukemia, autoimmunity or other disease states. For this reason it is critical that the rate of production of leukoctyes is maintained at levels that insure sufficient numbers for their proscribed protective functions without risk of overproduction. The focus of this project is on the role of the neuropeptide calcitonin- gene related peptide (CGRP) in regulating early B cell differentiation. Cells in the immune system have CGRP receptors and CGRP influences the activity of mature lymphocytes, macrophages and granulocytes. CGRP and another sensory neuropeptide, substance P, play a role in regulating the differentiation of distinct leukocyte populations. CGRP is found in nerve endings in bone marrow, hematopoietic cells have CGRP receptors, CGRP induces production of B cell regulatory cytokines and inhibits B cell progenitor responses to IL-7. The specific aims of this project are to show that administration of CGRP reduces the number of B cell progenitors, to identify CGRP receptor expressing cells in the B cell lineage, to examine how specific stages in early B cell development are influenced by CGRP, and to study the cellular mechanisms by which CGRP blocks B cell differentiation. The in vivo studies will determine the number of pre-B CFUs following CGRP treatment. CGRP receptor expressing cell populations will be identified by CGRP receptor mRNA analysis and by functional responses to CGRP. The role of CGRP in B cell differentiation will be studied using short term in vitro studies with cells derived from bone marrow. These studies will examine the effect of CGRP on proliferation and differentiation of distinct populations of B cell precursors present in bone marrow. Preliminary studies suggest that CGRP inhibits early B cell differentiation by cellular mechanisms involving events influenced by IL-7 and by activation of NFkappa-B. Studies will determine how CGRP inhibits NFkappa-B activation in a pre-B cell line and will examine how CGRP inhibits IL-7 responses in normal B cell progenitors. A better understanding of CGRP's role in B cell development may offer new avenues for new therapeutic approaches.