NOTCH2 AND B LYMPHOCYTE DEVELOPMENT

NOTCH2 和 B 淋巴细胞发育

• 批准号: 6176774
• 负责人: Christian S Kuhr
• 金额: $ 11.24万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6176774
• 关键词: B lymphocyte; apoptosis; biological signal transduction; bone marrow; cell differentiation; cell proliferation; flow cytometry; gene expression; genetically modified animals; glucocorticoids; growth factor; laboratory mouse; lymphopoiesis; nucleic acid probes; receptor; receptor expression; spleen; tissue /cell culture

Immune recognition relies on the ability of immunoglobulins and cell surface receptors to recognize foreign antigens without injuring self. Lymphocytes acquire this specificity during their maturation. Therefore, understanding the control of these developmental processes may provide insights into disease states that result from dysregulation of lymphocyte function. The Notch family of transmembrane receptors (which include Notch 1,2,3 and 4), originally described in Drosophila melanogaster, have been shown to significantly influence mammalian T lymphocyte development and positive selection. They are expressed in high levels in developing B lymphocytes suggesting they may also control B lymphopoiesis. The overall goal of this proposal is to determine the role of Notch family members in B lymphocyte development and differentiation. As with other ubiquitously expressed developmental proteins, Notch gene disruption studies have resulted in lethal mutations. Therefore, either dominant-negative or activated forms of the Notch 2 protein will be expressed as a transgene during B lymphopoiesis. The specific aims are: (1) To direct expression of a constitutively- activated or dominant-negative Notch2 in B lymphocytes during lymphopoiesis in mice, (2) To define the phenotypic alterations cause by manipulations of Nothc2 activity during B lymphocyte development, and (3) To characterize, using DNA array, the effects of Notch 2 activation on gene expression in developing B lymphocytes. These specific aims will test the hypothesis that the Notch2 transmembrane receptor directs differentiation of B lymphocyte during the development. Knowledge gained from these studies will provide insights into the control of normal lymphocyte maturation that may be of clinical import in understanding cellular aspects of solid organ graft rejection.

免疫识别依赖于免疫球蛋白和细胞表面受体识别外来抗原而不伤害自身的能力。淋巴细胞在其成熟过程中获得这种特异性。因此，了解这些发育过程的控制可能会提供对淋巴细胞功能失调导致的疾病状态的见解。最初在果蝇中描述的跨膜受体Notch家族（包括Notch 1、2、3和4）已经显示出显著影响哺乳动物T淋巴细胞发育和正选择。它们在发育中的B淋巴细胞中高水平表达，表明它们也可能控制B淋巴细胞生成。该提案的总体目标是确定Notch家族成员在B淋巴细胞发育和分化中的作用。与其他普遍表达的发育蛋白一样，Notch基因破坏研究导致了致命的突变。因此，Notch 2蛋白的显性阴性或活化形式将在B淋巴细胞生成期间作为转基因表达。具体目标是：（1）在小鼠淋巴细胞生成过程中指导组成型激活或显性阴性Notch 2在B淋巴细胞中的表达，（2）确定在B淋巴细胞发育过程中通过Nothc 2活性的操纵引起的表型改变，和（3）使用DNA阵列表征Notch 2激活对发育中的B淋巴细胞中基因表达的影响。这些特定的目的将检验Notch 2跨膜受体在发育过程中指导B淋巴细胞分化的假设。从这些研究中获得的知识将提供对正常淋巴细胞成熟的控制的见解，这可能在理解实体器官移植排斥的细胞方面具有临床意义。