Sex Chromosome Effects in Lupus

描述（由申请人提供）：系统性红斑狼疮（SLE）女性发病频率远高于男性，比例为9:1。许多狼疮小鼠模型也表明，与雄性相比，雌性狼疮的发病率更高。性激素、性染色体或两者都可能导致这种女性偏见。由于研究性腺激素的影响比研究X和Y基因的影响要容易得多，性染色体在狼疮中的作用仍然知之甚少。在性腺类型相同的情况下，性染色体补体不同的小鼠（XX vs. XY）被创造出来，以确定性染色体在没有暴露于不同类型性激素的混淆效应的情况下的影响。最初是在近亲繁殖的MF1小鼠上，我们的实验室最近将具有性染色体补体的小鼠回交到SJL菌株上，这是一种具有pristane诱导狼疮的雌性优势的菌株。在本提案的目的#1中，我们将在具有性染色体信息补体的SJL小鼠中使用pristane诱导狼疮，以确定该狼疮模型的临床病程、蛋白尿、BUN水平、肾脏病理和免疫措施是否受到性染色体基因型的影响。在目标#2中，我们将把SJL XY- Sry雄性小鼠与雌性NZB小鼠杂交，以产生具有信息性染色体补体的（NZBxSJL）F1小鼠。然后，性染色体补体对这种自发性狼疮模型的已知女性优势的影响将使用与目标1中相同的疾病和免疫反应测量来确定。总之，这个探索性（R21）应用将或将不支持性染色体在实验性和自发性狼疮模型中的女性优势中的作用。这是一个探索性的（R21）应用程序，以确定性染色体对两种狼疮小鼠模型（一种化学诱导的和一种自发的）的影响。这种疾病是选择在9:1女性优势的人类疾病系统红斑狼疮。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) affects females much more frequently than males with a ratio of 9:1. Many murine models of lupus also demonstrate a greater incidence in females as compared to males. Sex hormones, sex chromosomes or both may contribute to this female bias. Since, it has been much easier to study the effect of gonadal hormones, than the effects of X and Y genes, the role of sex chromosomes in lupus remain poorly understood. Mice which differ in the complement of sex chromosomes (XX vs. XY), while having the same gonadal type, have been created to determine the effect of sex chromosomes in the absence of confounding effects of exposure to different types of sex hormones. Originally on outbred MF1 mice, the mice with an informative complement of sex chromosomes have recently been backcrossed by our laboratory onto the SJL strain, a strain with a female preponderance for pristane induced lupus. In aim #1 of this proposal, we will induce lupus with pristane in SJL mice with the informative complement of sex chromosomes to determine whether clinical disease course, proteinuria, BUN levels, kidney pathology and immune measures are influenced by sex chromosome genotype in this model of lupus. In aim #2, we will cross SJL XY- Sry male mice with female NZB mice to create (NZBxSJL)F1 mice having the informative sex chromosome complement. Then, the effect of sex chromosome complement on the known female preponderance of this spontaneous model of lupus will be ascertained using the same measures of disease and immune responses as in aim #1. Together this exploratory (R21) application will or will not support a role for sex chromosomes in the female preponderance in experimental and spontaneous models of lupus. This is an exploratory (R21) application to determine the effect of sex chromosomes on two murine models of lupus (one chemically induced and one spontaneous). This disease was chosen in light of the 9:1 female preponderance of the human disease system lupus erythematosus.