The human glucocorticoid receptor and normal and pathological terminal erythroid

描述(由申请人提供)： 人类糖皮质激素受体基因(GR)高度多态，编码转录活性GR？亚型，类似于小鼠GR，GR？，一种反式激活潜能降低的异构体，以及GR？，显性-阴性亚型。在人类非红系细胞中的研究已经证实，在体外，GR亚型的表达模式预测了细胞对DXM的反应。此外，在炎症性疾病、自身免疫性疾病和慢性抑郁症患者中，GR基因多态性正逐渐成为DXM无反应或产生DXM耐药性的主要原因。临床观察表明，GR配体地塞米松(DXM)自1961年以来一直在刺激红细胞生成。DXM被用作红细胞生成刺激剂(ESA)，以挽救钻石黑扇贫血(DBA)患者观察到的红系终末(EB)成熟缺陷，DBA是一种抗促红细胞生成素(EPO)的同源形式的红系再生障碍性贫血，通常与导致核糖体不足的突变有关。然而，不同的GR亚型对红系终末成熟的影响，以及这些影响是否可能决定DBA患者(约50%的DBA患者对DXM无效)是否对DXM无效，目前尚不清楚。我们最近发现，稳定GRB mRNA的rs6198单核苷酸多态(SNP)在终末期EB成熟疾病中出现的频率增加，与产量过剩和红细胞增多症相关，如真性红细胞增多症(55%)以及产量不足(贫血)，如DBA(43%)(Varricchio等人，血液2011；218；425-436和473-474)。这些观察结果导致了我们对DXM作为ESA的理解的范式转变，突出了临床上需要进一步研究GR基因多态对EB末端成熟的影响。我们建议鉴定不同的GR亚型在EB终末成熟中的生物学活性(目标1)，确定调控这些GR异构体在EB终末成熟过程中表达的微环境和遗传因素(S)(目标2)，并探讨单个GR亚型在体外挽救DBA患者EB终末成熟中的作用(目标3)。我们预测，通过提高我们对正常和DBA红细胞生成中GR生物学的理解，这些研究可能会发现更有效的GR激动剂(AIM 1)和药理调节剂(微环境因素，AIM 2)，以改善DBA患者和其他EPO耐药贫血的治疗。 (摘要结束)

DESCRIPTION (provided by applicant): The highly polymorphic human glucocorticoid receptor gene (GR) encodes the transcriptionally active GR¿ isoform similar to murine GR, GR?, an isoform with reduced transactivation potential and GR¿, a dominant-negative isoform. Studies in human non-erythroid cells have identified that the pattern of GR isoform expression predicts cellular response to DXM in vitro. In addition, GR polymorphism is emerging as the leading cause for DXM unresponsiveness or for development of DXM resistance in patients with inflammatory and autoimmune diseases and in chronic depression. Clinical observations indicating that the GR ligand dexamethasone (DXM) stimulates erythropoiesis have been available since 1961. DXM is used as erythropoiesis stimulating agent (ESA) to rescue the deficient terminal erythroid (EB) maturation observed in patients with Diamond Blackfan Anemia (DBA), a congenic form of erythropoietin (EPO) resistant erythroid aplasia often associated with mutations that result in ribosome insufficiency. However the effects of the various GR isoforms on terminal erythroid maturation and whether these effects may determine DXM unresponsiveness in DBA patients (~50% of DBA patients do not respond to DXM) is still unknown. We recently identified that the rs6198 single nucleotide polymorphism (SNP) that stabilizes GRb mRNA is present with increased frequency in diseases of terminal EB maturation, associated with overproduction and erythrocytosis, as in polycythemia vera (55%) as well as underproduction (anemia) as in DBA (43%) (Varricchio et al, Blood 2011; 218; 425-436 and 473-474). These observations have generated a paradigm shift in our understanding of DXM as ESA highlighting the clinical need for additional studies on the effect of GR polymorphism on terminal EB maturation. We propose to characterize the biological activity of different GR isoforms in terminal EB maturation (Aim 1), to identify the microenvironmental and genetic factor(s) that regulate expression of these GR isoforms during terminal EB maturation (Aim 2) and to investigate the role exerted by individual GR isoforms in rescuing terminal EB maturation in DBA patients in vitro (Aim 3). We predict that these studies, by improving our understanding of the biology of GR in normal and DBA erythropoiesis, may identify more potent GR agonists (Aim 1) and pharmacological modulators (microenvironmental factors, Aim 2) to improve the treatment of DBA patients and possibly of other EPO resistant anemias. (End of Abstract)