Gender-Specific Role of p202 in Lupus Susceptibility

系统性红斑狼疮（SLE）是一种自身免疫性疾病。这种疾病的发病率是女性对男性的比例 10：1。虽然，一些因素，如基因多态性，女性性激素雌激素和干扰素信号， 与狼疮疾病发展中的性别偏见有关，分子机制仍然存在 有待阐明。因此，了解候选狼疮易感基因的因果作用是很重要的 其表达受上述因子调控。我们建议在未来一年进行的研究的主要目的， （一）了解性激素（雌激素和睾丸激素）如何差异调节 表达Ifi 202，一个候选的狼疮易感基因（编码p202蛋白）在新西兰 黑（NZB）衍生的Nba 2间隔的小鼠1号染色体上;和（ii）定义的作用，p202蛋白在性别 狼疮易感性的偏差p202蛋白（~52-k Da）是转录活性的诱导型调节因子 如p53、E2 F1、NF-κB和AP-1等因子。多种细胞类型中p202蛋白水平升高 抑制细胞周期进程和调节细胞存活。根据我们的初步和其他观察，我们 假设启动子多态性和性激素有助于Ifi 202在 某些易患狼疮的雌性小鼠。此外，我们推测B细胞中p202蛋白水平的增加， 而T细胞通过增加细胞凋亡的阈值而导致狼疮易感性。p202蛋白 通过调节NF-κB和c-Jun/AP-1的转录活性增加凋亡阈值。 目的#1：确定女性性激素雌激素和男性性激素雄激素如何通过它们的受体 （分别为雌激素受体-α和AR）差异调节Ifi 202在B和T细胞中的表达。目的 #2：为了研究B6.Nba2同源免疫细胞中p202蛋白水平的增加（B6.Nba2的同源免疫细胞）是如何发生的。 Nba 2间隔对C57 BL/6遗传背景）小鼠下调Fcgr 2b基因的表达 （编码抑制性Fc受体FcγRIIB）。目标#3：阐明 在B6.Nba 2淋巴细胞（B和T细胞）中p202蛋白水平的增加差异性地调节了 NF-κB和c-Jun/AP-1的转录活性。重要性：证明我们的假设具有重要意义 对了解狼疮发病机制中性别偏见的分子基础的意义。 重要的是，我们的研究结果有可能确定诊断的分子靶点， 狼疮疾病的治疗干预。

Systemic lupus erythematosus (SLE) is an autoimmune disease. The disease develops at a female-to-male ratio of 10:1. Although, several factors, such as gene polymorphisms, female sex hormone estrogen, and interferonsignaling, are implicated in gender bias in the development of lupus disease, the molecular mechanisms remain to be elucidated. Therefore, it is important to understand the causal role of candidate lupus susceptibility genes whose expression is regulated by the above factors. The major objectives of our proposed studies in the next funding period are to: (i) understand how sex hormones (estrogen and testosterone) differentially regulate the expression of Ifi202, a candidate lupus susceptibility gene (encoding p202 protein) within the New Zealand Black (NZB)-derived Nba2 interval on murine chromosome 1; and (ii) define the role of the p202 protein in sex bias in lupus susceptibility. The p202 protein (~52-k Da) is an inducible modulator of transcriptional activities of factors, such as p53, E2F1, NF-κB, and AP-1. Increased levels of p202 protein in a variety of cell types inhibit cell cycle progression and modulate cell survival. Based on our preliminary and other observations, we hypothesize that promoter polymorphisms and sex hormones contribute to increased expression of Ifi202 in certain lupus-prone strains of female mice. Moreover, we postulate that increased levels of p202 protein in B and T cells contribute to lupus susceptibility by increasing the threshold for apoptosis. The p202 protein increases the threshold for apoptosis by modulating the transcriptional activities of NF-κB and c-Jun/AP-1. Aim #1: Determine how female sex hormone estrogen and male sex hormone androgen through their receptors (estrogen receptor-α and AR, respectively) differentially regulate the expression of Ifi202 in B and T cells. Aim #2: To investigate how increased levels of p202 protein in immune cells of B6.Nba2 congenic (congenic for the Nba2 interval on C57BL/6 genetic background) mice down-regulate the expression of the Fcgr2b gene (encoding the inhibitory Fc receptor FcγRIIB). Aim #3: To elucidate the molecular mechanisms by which increased levels of p202 protein in B6.Nba2 lymphocytes (B and T cells) differentially modulate the transcriptional activities of NF-κB and c-Jun/AP-1. Significance: Proving our hypotheses has important implications for the understanding of the molecular basis of sex bias in pathogenesis of lupus disease. Importantly, the results from our studies have the potential to identify the molecular targets for diagnosis and therapeutic interventions in lupus disease.