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: 6341686
• 负责人: William C. Sha
• 金额: $ 21.82万
• 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/6341686
• 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（改编自研究者摘要）：NF-κ B/Rel 转录因子是一个由五种蛋白质组成的家族， 复杂的基因调控参与先天和特异性 免疫力 本研究将探讨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 基因靶向小鼠的个别家庭成员结合两个 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-κ B/Rel活化的标记物。 该标记 是通过将lacZ报告基因靶向引入到 I-κ-B-α基因座。 第二种方法使用标记了 用绿色荧光蛋白重建原代B细胞， NF-κ B/Rel蛋白的特定形式。 逆转录病毒重建将 用于确定单个复合物如何调节类别转换， B细胞中的免疫球蛋白分泌。 定义自然生理 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，以及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 调节免疫反应也将产生更好的理解， 临床相关药物的体内作用，如阿司匹林和 糖皮质激素，已被确定为这种抑制剂， 转录因子家族 具体目标1将决定何时何地 NF-κ B/Rel复合物在体内的自然病程中被激活， 对T细胞依赖性抗原的免疫应答。 具体目标2将 在体内研究单个NF-κ B/Rel因子的缺乏如何破坏 有效的免疫反应，并确定缺陷的细胞基础 应答 目的3将定义特定NF-κ B/Rel复合物在 初级B细胞调节免疫球蛋白分泌和类别转换。