The human glucocorticoid receptor and normal and pathological terminal erythroid

描述（由申请人提供）： 高度多态性的人糖皮质激素受体基因（GR）编码与鼠GR相似的转录活性GR？亚型，GR？，具有降低的反式激活潜力的同种型和GR？，显性负性同种型。在人类非红系细胞中的研究已经确定，GR亚型表达的模式预测体外细胞对DXM的反应。此外，GR多态性正在成为炎症性和自身免疫性疾病以及慢性抑郁症患者中DXM无反应性或DXM抗性发展的主要原因。自1961年以来，临床观察表明GR配体地塞米松（DXM）刺激红细胞生成。DXM被用作红细胞生成刺激剂（ESA），以挽救在钻石黑扇贫血（DBA）患者中观察到的终末红细胞（EB）成熟缺陷，这是一种红细胞生成素（EPO）抗性红细胞发育不全的同源形式，通常与导致核糖体不足的突变相关。然而，各种GR亚型对终末红细胞成熟的影响以及这些影响是否可能决定DBA患者中DXM无反应性（约50%的DBA患者对DXM无反应）仍然未知。我们最近发现，稳定GRb mRNA的rs6198单核苷酸多态性（SNP）在终末EB成熟疾病中的频率增加，与过度生产和红细胞增多症相关，如真性红细胞增多症（55%）以及DBA（43%）中的生产不足（贫血）。（Varricchio等人，Blood 2011; 218; 425-436和473-474）。这些观察结果已经产生了一个范式转变，我们的理解DXM作为ESA突出的临床需要的GR多态性对终端EB成熟的影响进行额外的研究。我们建议表征不同GR亚型在终末EB成熟中的生物学活性（目的1），确定在终末EB成熟过程中调节这些GR亚型表达的微环境和遗传因子（目的2），并研究单个GR亚型在体外挽救DBA患者终末EB成熟中的作用（目的3）。我们预测，这些研究，通过提高我们对正常和DBA红细胞生成中GR生物学的理解，可能会发现更有效的GR激动剂（目标1）和药理学调节剂（微环境因素，目标2），以改善DBA患者的治疗，并可能改善其他EPO耐药性贫血。 (End摘要）

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)