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 interferon-signaling, 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-:B, 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-:B and c-Jun/AP-1.
Aim #1 : Determine how female sex hormone estrogen and male sex hormone androgen through their receptors (estrogen receptor-1 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 Fc3RIIB). We also plan to investigate the consequence of the down-regulation of the Fc3RIIB receptor in B cells.
Aim #3 : To elucidate the molecular mechanisms by which increased levels of p202 protein in B6.Nba2 lymphocytes (B and T cells), by modulating the transcriptional activities of NF-:B and c-Jun/AP-1, down-regulate the expression of immunoregulatory cytokines, such as IL-2 and TNF-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.
Our studies will identify molecular mechanisms by which genetic factors and sex hormones-dependent increased expression of p202 protein in immune cells contributes to gender bias in the development of lupus disease. Our studies will increase the understanding of the molecular basis of sex bias in lupus disease and could potentially lead to better diagnostic tools as well as disease monitoring, and effective treatments. 1
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