Generation of Ikaros conditional knockout mice

描述（由申请人提供）：调节对病原体的适当抗原特异性免疫反应对人类健康至关重要。不适当的免疫反应是许多人类疾病的基础，包括类风湿关节炎、糖尿病、狼疮和心脏病。了解参与免疫反应调节的分子机制是发现这些疾病新疗法的一条途径。Ikaros是一种核转录调节因子，从造血干细胞水平来看，它几乎只在造血谱系的细胞中表达。通过对Ikaros基因工程小鼠的分析，很明显，Ikaros活性是正常免疫系统发育所必需的。Ikaros基因缺失小鼠的缺陷包括完全缺乏B细胞和自然杀伤细胞，选择性缺乏树突状和？T细胞发育中的dT细胞和缺陷。然而，在体内免疫应答过程中，Ikaros在成熟免疫系统细胞功能中的作用尚不清楚。这是由于Ikaros null小鼠的复杂表型，除了在造血和淋巴系细胞的发育中存在大量缺陷外，还显示完全缺乏淋巴结的发育。这是理解Ikaros功能的关键障碍。为了克服这些障碍，我们建议开发一种系统，通过该系统可以选择性地在小鼠的特定免疫细胞亚群中删除Ikaros的功能。我们将通过使用Cre-lox技术创建一个条件Ikaros null等位基因来实现这一点。这将在加州大学戴维斯分校小鼠生物学项目（MBP）的协助下完成。一旦生成，该小鼠模型系统将通过使用不同的cre转基因小鼠，对研究Ikaros在多种血细胞谱系中的作用具有极其重要的价值。我们将优先研究在免疫反应过程中Ikaros在成熟T淋巴细胞和B淋巴细胞中的作用，以及研究这些谱系中缺乏Ikaros如何导致免疫功能障碍导致疾病。综上所述，这些研究将为Ikaros在免疫反应中的体内功能提供有价值的见解。

DESCRIPTION (provided by applicant): The regulation of appropriate antigen-specific immune responses to pathogen is crucial for human health. Inappropriate immune responses underlie many human diseases including rheumatoid arthritis, diabetes, lupus and heart disease. Understanding the molecular mechanisms involved in regulation of the immune response is one road to discovering new therapies for these diseases. Ikaros is a nuclear transcriptional regulator that is expressed almost exclusively in cells of the hematopoietic lineage from the level of the hematopoietic stem cell. It is clear, through analyses of genetically engineered Ikaros null mice, that Ikaros activity is required for normal immune system development. Defects in Ikaros null mice include a total lack of B and natural killer cells, selective lack of some lineages of dendritic and ?dT cells and defects in a¿T cell development. However, the role of Ikaros in the function of mature immune system cells during the course of an in vivo immune response is still unknown. This is due to the complex phenotype of Ikaros null mice that display, in addition to the multitude of defects in development of hematopoietic and lymphoid lineage cells, a total lack of development of lymph nodes. This has been a critical barrier in the field in understanding Ikaros' function. In order to overcome these obstacles, we propose to develop a system by which Ikaros' function can be deleted selectively in specific immune cell subsets in the mouse. We will do this by creating a conditional Ikaros null allele through the use of Cre-lox technology. This will be done with the assistance of the Mouse Biology Program (MBP) at University of California, Davis. Once generated, this mouse model system will be extremely valuable to study the role of Ikaros in multiple blood cell lineages, through the use of different Cre-transgenic mice. We will prioritize studies focused on the role of Ikaros in mature T and B lymphocytes during the course of an immune response as well as in investigation of how lack of Ikaros within these lineages may result in immune dysfunction leading to disease. Taken together, these studies will provide valuable insight into the in vivo function of Ikaros in the immune response.