先天性纯红细胞再生障碍性贫血发病机制的研究

Diamond-Blackfan anemia (DBA) is a genetically and clinically heterogeneous disorder characterized by erythroid failure, congenital anomalies and a predisposition to cancer. The anemia is due to failure of erythropoiesis, with normal platelet and myeloid lineages. Patient management is centered on accurate diagnosis, appropriate use of transfusions and iron chelation, corticosteroids, hematopoietic stem cell transplantation, and a coordinated multidisciplinary approach to these complex patients. Approximately 80% of patients will initially respond to corticosteroid therapy. . The molecular biology of DBA is being extensively explored and the syndrome appears to result from haploinsufficiency of either a small or large subunit associated ribosomal protein. DBA is the first human disease known to be due to mutations in a ribosomal structural protein. Various mutations have been found in coding and noncoding regions of at least 13 RPs, including RPL5, RPS7, RPL9, RPS10, RPL11, RPS15, RPS17, RPS19, RPS24, RPS26, RPL36, RPS27a, and RPL35a, accounting for about 55% of all DBA cases . The presence of a gene mutation confirms the diagnosis of DBA, but these mutations currently are found in only 50% of the patients. It may suggest there are some additional pathogenic genes exist in DBA except RPs genes .We have collected bone marrow samples of children acquired DBA , and then compared the whole genome RNA-Seq dates of DBA samples with control. Through the analysis of gene expression level, we identified some potential pathogenic genes in DBA. Knockdown of RPs genes in human CD34+ cells will block proliferation and differentiation of erythroid precursors, so We can develop cell culture models using RNAi interference.Then we will test the function of the potential pathogenic gene in RPs defiency cell models to study the pathogenesis of Diamond-Backfan anemia.. The recent studies have provided fascinating insights into the pathogenesis of DBA. However, several important questions are yet to be answered. It remained to be determined, for example, how haploinsufficiency of ribosomal proteins expressing ubiquitously causes specific defects in erythropoiesis, and why mutations in some ribosomal proteins genes, have more profound impact on fetal development than mutations in other ribosomal protein genes. Although corticosteroids remain the mainstay of treatment of DBA more than half a century after the original report of their efficiacy, their mechanism of action is still unknown. DBA have now begun to lead us towards a further understanding of bone marrow failure syndrome and potentially to novel ways of treatment.

先天性纯红细胞再生障碍性贫血（Diamond-Blackfan Anemia，DBA）是儿童遗传性骨髓衰竭性疾病的一种，其发病率约为新生儿中4-5/1000000，患者多在1岁以前出现贫血症状，是一组具有遗传和临床异质性的疾病。其临床特征为红系造血衰竭，先天畸形和肿瘤易感性增加。该病的治疗包括糖皮质激素，输血和造血干细胞移植。目前发现该病的致病基因均为编码核糖体大小亚基蛋白的编码基因，但是伴有突变的患者仅占50%-60%，这提示可能存在其他类型的致病基因参与发病。我们已通过RNA测序，从DBA病人标本中筛选出除核糖体蛋白编码基因之外存在表达差异的部分基因。本课题拟通过RNAi技术建立DBA的RPS19，RPS24，RPL5，RPL11的细胞模型，将候选基因在不同的DBA细胞模型中进行功能验证，确定其在疾病发生中的致病或协同致病作用，从而进一步探讨该病的发病机制和新的治疗靶点。