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B CELL DEFICIENCY IN A/WYSNJ MICE

A/WYSNJ 小鼠 B 细胞缺陷

基本信息

批准号：
6349860
负责人：
Michael Paul Cancro
金额：
$ 26.57万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-02-01 至 2002-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (Adapted from the Investigator's abstract): The A/WySnJ mouse provides a model for studying B-cell selection into the stable peripheral B-cell pool. The investigators have shown that the A/WySnJ strain has a single, autosomal co-dominant defect, Bcmd-1, resulting in a profound peripheral B-cell deficiency and poor IgG responses. The Bcmd-1 defect is not present in the related A/J sub-line, is intrinsic to B-cells, and shortens the life span of peripheral B-cells by causing premature death at every maturation step after surface IgM acquisition. Two hypotheses can explain these observations: Bcmd-1 may be a loss-of-function mutation that either disrupts a life span lengthening pathway or disrupts a molecule that dampens a life span shortening pathway. The investigators propose biological, biochemical and genetic studies to distinguish these hypotheses and investigate the mechanism of Bcmd-1 action. In Specific Aim one, the two genes that control B-cell deficiency in interspecies crosses, Bcmd-1 and Bcmd-2, will be mapped by analysis of simple sequence length polymorphisms in the extreme progeny of the (A/WySnJXCAST/Ei) F2 interspecific cross. A congenic strain will be constructed and used to map the Bcmd-1 locus that is polymorphic between strains A/WySnJ and A/J. In Specific Aim two, the investigators test whether the steps in transit to the long-lived pool affected by Bcmd-1 comprise an "all -or-none" event versus continuous signals. BrdU labeling studies of F1 individuals will be employed, since continuous signals predict an intermediate life span for all B-cells in F1 mice, whereas an all-or none event predicts separate pools of long-versus short-lived B-cells. In Specific Aim three, assays will be established for B-cell life span, apoptosis, Bcl gene family induction, and cell division; then pathways that affect these parameters will be systematically probed in immature B-cells. When a pathway is found to affect A/J but not A/WySnJ B-cells, biochemical markers will be analyzed to determine whether Bcmd-1 disrupts the pathway. In Specific Aim 4, the investigators assess Bcmd-1's effect on B-cell traffic, repertoire formation, and the germinal center reaction, through mixed marrow chimeras, limiting dilution and fine specificity analysis, and cytofluorimetric immunohistochemical studies in chimeric mice.

描述（改编自研究者摘要）：A/WySnJ小鼠为研究B细胞选择进入稳定的外周血提供了一个模型。 B细胞池研究人员已经表明，A/WySnJ菌株具有单一的常染色体共显性缺陷Bcmd-1，导致严重的外周B细胞缺乏和IgG应答差。 Bcmd-1缺陷是不存在于相关的A/J亚系中，是B细胞固有的，和缩短外周血B细胞的寿命，导致过早死亡，每个成熟步骤后表面IgM的收购。两个假设可以解释这些观察结果：Bcmd-1可能是一种功能缺失突变，要么破坏了延长寿命的途径，要么破坏了抑制了缩短寿命的途径。研究人员建议，生物学、生物化学和遗传学研究来区分这些假说探讨Bcmd-1的作用机制。在具体目标一中，两个在物种间杂交中控制B细胞缺乏的基因，Bcmd-1和 BCMD-2的基因型将通过简单序列长度多态性分析进行定位在（A/WySnJXCAST/Ei）F_2种间杂交的极端后代中。一将构建同源菌株并用于定位Bcmd-1基因座， A/WySnJ和A/J菌株之间的多态性。调查人员测试是否在运输到长寿池的步骤，受Bcmd-1影响的事件包括“全有或全无”事件与连续事件信号. 将采用F1个体的BrdU标记研究，因为连续信号预测F1中所有B细胞的中间寿命小鼠，而全或无事件预测单独的长期与短寿命的B细胞在具体目标三中，将建立测定方法， B细胞寿命、凋亡、Bcl基因家族诱导和细胞分裂; 那么影响这些参数的途径将被系统地探测，不成熟的B细胞当发现一种途径影响A/J但不影响A/WySnJ时将分析B细胞、生化标志物以确定Bcmd-1是否破坏了通道在具体目标4中，研究人员评估了Bcmd-1的对B细胞运输、库形成和生发中心的影响反应，通过混合骨髓嵌合体，有限稀释和精细特异性分析和细胞荧光免疫组织化学研究，嵌合小鼠