Gender Bias in Lupus: Contribution of Sex Chromosomes

狼疮中的性别偏差：性染色体的贡献

• 批准号: 7903679
• 负责人: Ram Raj Singh
• 金额: $ 23.04万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2011-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903679
• 关键词: A Mouse; Adult; Affect; Animals; Autoantibodies; Autoantigens; Autoimmune Diseases; Backcrossings; Biological Models; Blood Urea Nitrogen; CD40 Ligand; Cells; Chromosomes, Human, Pair 6; Clinical; Complement; Creatinine; Data; Development; Disease; Disease Outcome; Dose; Estradiol; Experimental Autoimmune Encephalomyelitis; Female; Generations; Genes; Genetic; Genotype; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Gonadal structure; Hormonal; Human; Immune; Immune response; Injection of therapeutic agent; Interleukin-13; Kidney; Lead; Lupus; Masks; Measures; Mineral Oil; Modeling; Mouse Strains; Mus; NR4A1 gene; Nephritis; Organ; Ovary; PTPN11 gene; Pathology; Phase; Physiological; Ploidies; Predisposition; Pristane; Production; Proteinuria; Public Health; Research; Role; SJL Mouse; Safe Sex; Screening procedure; Serum; Sex Bias; Sex Characteristics; Sex Chromosomes; Spleen; Surface; Systemic Lupus Erythematosus; TLR7 gene; TNFSF5 gene; Testing; Testis; Testosterone; Transgenes; Transgenic Organisms; Vertebrates; Woman; Work; X Chromosome; Y Chromosome; Yin-Yang; autosome; base; cytokine; dosage; experience; human TLR7 protein; interest; interleukin-13 receptor; lymph nodes; male; men; migration; mortality; mouse model; novel; protein expression; public health relevance; research study; response; sry Genes; testis determining factor

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs more in females than males at a ratio of 9:1. The female bias for the development of lupus is also seen in most genetically lupus-susceptible Vertebrate Animals: We have found that even chemically induced lupus in an otherwise healthy mouse strain (SJL) displays a female bias. The fundamental basis for such gender bias remains unclear. Sex hormones, sex chromosomes or both may contribute to such sex difference. Extensive human and animal studies have investigated the role of gonadal hormones on the development of SLE. It has been difficult to dissect the role of contribution of sex chromosome X and Y genes, independent of sex hormones. We have made use of mice that differ in the complement of sex chromosomes (XX vs. XY), while having the same gonadal type, to determine the effect of sex chromosome complements. In preliminary work, we have introgressed the informative complement of sex chromosomes from the stock MF1 background onto the SJL background to generate XX females, testes determining factor gene Sry-deficient XY (XY-) females, and Sry transgenic XX (XX.Sry) males, and XY-.Sry males. We have found that mice of the XX sex chromosome complement (XX and XX.Sry), as compared to XY (female XY- and male XY-.Sry), experience more severe autoimmune disease, namely autoimmune encephalomyelitis and pristane-induced lupus. Guided by these novel data, we hypothesize that XX sex chromosome complement, as compared to XY, confers greater susceptibility to lupus. In this proposal, we will test this hypothesis and begin to dissect the mechanisms. In Aim 1, we will investigate mechanisms that confer greater susceptibility to pristane-induced lupus in SJL mice with the informative complement of sex chromosomes. In Aim 2, we will introgress the Y- chromosome (deleted for Sry) and the Sry transgene onto the genetically lupus-prone NZM.2328 strain to the N10 generation. Then, the effect of sex chromosome complement on this spontaneous model of lupus will be ascertained using disease measures (proteinuria, creatinine, blood urea nitrogen and renal pathology), autoantibodies and immune responses. Finally, in Aim 3, we will generate mice of the XO genotype to determine if the sex chromosome effect on disease outcomes and immune measures in Aims 1 and 2 is attributable to a gene unique to the Y chromosome versus the dosage of X genes. Together these proposed studies will greatly advance the understanding of the role of sex chromosomes in lupus. PUBLIC HEALTH RELEVANCE The goal of the current proposal is to investigate the contribution of sex chromosomes in the gender bias in autoimmune diseases such as systemic lupus erythematosus, which affect women much more frequently than men with a ratio of 9:1. The results of the proposed study will not only aid our understanding of lupus, but will also potentially lead to identification of newer targets of treatment.

描述（由申请人提供）：全身性红斑狼疮（SLE）是一种自身免疫性疾病，在女性中比男性以9：1的比例发生更多。在大多数遗传性狼疮的脊椎动物动物中也可以看到狼疮发育的雌性偏见：我们发现，即使在原本健康的小鼠菌株（SJL）中，甚至化学诱导的狼疮也会显示出女性偏见。这种性别偏见的基本基础尚不清楚。性激素，性染色体或两者都可能导致这种性别差异。广泛的人类和动物研究研究了性腺激素在SLE的发展中的作用。很难剖析与性激素无关的性染色体X和Y基因的作用。我们利用了在性别染色体（XX与XY）中不同的小鼠，同时具有相同的性腺类型，以确定性别染色体补充的作用。在初步工作中，我们将来自库存MF1背景的性染色体的信息补充介绍到SJL背景上以产生XX女性，睾丸确定因子基因缺乏XY（XY-）XY（XY-）女性，以及Sry trangic XX（xx.sry）的男性和XY Males。我们发现，与XY（女性XY-和雄性Xy-sry）相比，XX性染色体补体（XX和XX.Sry）的小鼠经历了更严重的自身免疫性疾病，即自身免疫性脑脊髓炎和Pristane诱发的狼疮。在这些新型数据的指导下，我们假设XX性染色体补体与XY相比，对狼疮的敏感性更大。在此提案中，我们将检验该假设并开始剖析机制。在AIM 1中，我们将调查具有更大敏感性在SJL小鼠中具有更大的性染色体补充的机制。在AIM 2中，我们将将Y-染色体（用于SRY删除）和SRY转基因浸入遗传性狼疮的NZm.2328菌株中。然后，将使用疾病措施（蛋白尿，肌酐，血液尿素氮和肾脏病理学），自身抗体和免疫反应来确定性染色体补充对这种狼疮模型的影响。最后，在AIM 3中，我们将生成XO基因型的小鼠，以确定AIM 1和2中的性染色体对疾病结果和免疫测量的影响是否归因于Y染色体所特有的基因，而不是X基因的剂量。这些提出的研究共同将大大提高人们对性别染色体在狼疮中的作用的理解。公共卫生相关性目前的提案的目的是调查性别染色体在性别偏见中在自身免疫性疾病中的贡献，例如全身性红斑狼疮，这比9：1的男性更频繁地影响女性。拟议的研究的结果不仅将有助于我们对狼疮的理解，而且还将有可能导致鉴定新的治疗靶标。