IN VIVO ROLE OF NF-KB/REL FACTORS IN IMMUNE RESPONSES

NF-KB/REL 因子在免疫反应中的体内作用

• 批准号: 6488991
• 负责人: William C. Sha
• 金额: $ 22.47万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6488991
• 关键词: B lymphocyte; Retroviridae; T lymphocyte; antibody formation; gene rearrangement; genetically modified animals; green fluorescent proteins; histochemistry /cytochemistry; immunoglobulin genes; immunoregulation; laboratory mouse; leukocyte activation /transformation; nuclear factor kappa beta; transcription factor; transfection /expression vector

DESCRIPTION (Adapted from the Investigator's abstract): NF-kappaB/Rel transcription factors are a family of five proteins which function as dimer complexes in the regulation of genes involved in innate and specific immunity. This study will examine how these transcription factors regulate in vivo immune responses. Our experimental approach will utilize gene-targeted mice for individual family members in combination with two unique experimental approaches. The first approach uses a histochemical marker that directly monitors in vivo NF-kappaB/Rel activation. This marker was created by targeted introduction of a lacZ reporter gene into the I-kappa-B-alpha locus. The second approach uses retroviral vectors tagged with a green fluorescent protein to reconstitute primary B-cells with specific forms of NF-kappaB/Rel proteins. Retroviral reconstitution will be used to determine how individual complexes regulate class switching and immunoglobulin secretion in B-cells. Defining the natural physiological roles of these factors will directly contribute to understanding why certain members are proto-oncogenes, and how their disregulation can lead to oncogenic activation in human cancer. Determining how these factors regulate immune responses will also produce a better understanding of the in vivo action of clinically relevant drugs, such as aspirin and glucocorticoids, that have been identified as inhibitors of this transcription factor family. Specific Aim 1 will determine when and where NF-kappaB/Rel complexes are activated in vivo during the natural history of an immune response to a T-cell dependent antigen. Specific Aim 2 will examine in vivo how the absence of individual NF-kappaB/Rel factors disrupts effective immune responses and determine the cellular basis for defective responses. Aim 3 will define roles of specific NF-kappaB/Rel complexes in primary B-cells in regulating immunoglobulin secretion and class switching.

描述（改编自研究者的摘要）：NF-kappaB/Rel 转录因子是由五种蛋白质组成的家族，其功能为二聚体 参与先天性和特异性的基因调节复合物 免疫。 这项研究将研究这些转录因子如何调节 体内免疫反应。 我们的实验方法将利用 基因靶向小鼠与两个家庭成员相结合 独特的实验方法。 第一种方法使用组织化学 直接监测体内 NF-kappaB/Rel 激活的标记。 这个标记 是通过将 lacZ 报告基因定向引入到 I-kappa-B-alpha 基因座。 第二种方法使用标记的逆转录病毒载体 用绿色荧光蛋白重建原代 B 细胞 NF-kappaB/Rel 蛋白的特定形式。 逆转录病毒重组将 用于确定各个复合体如何调节类别转换和 B 细胞中的免疫球蛋白分泌。 自然生理学的定义 这些因素的作用将直接有助于理解为什么某些 成员是原癌基因，它们的失调如何导致 人类癌症中的致癌激活。 确定这些因素如何 调节免疫反应也将有助于更好地了解免疫反应 临床相关药物的体内作用，例如阿司匹林和 糖皮质激素，已被确定为该药物的抑制剂 转录因子家族。 具体目标 1 将确定时间和地点 NF-kappaB/Rel 复合物在自然历史过程中在体内被激活 对 T 细胞依赖性抗原的免疫反应。 具体目标 2 将 体内检查单个 NF-kappaB/Rel 因子的缺失如何造成干扰 有效的免疫反应并确定缺陷的细胞基础 回应。 目标 3 将定义特定 NF-kappaB/Rel 复合物在 原代 B 细胞调节免疫球蛋白分泌和类别转换。