Characterizing the role of BCL11A in hematopoietic development and functions

描述(由申请人提供)：对调节人类血红蛋白转换的分子机制的分析对于开发基于靶向的治疗β-血红蛋白疾病，包括镰状细胞疾病和β-地中海贫血至关重要。在成人中重新激活胎儿血红蛋白(HBF)可以减轻这些情况的严重性。我们最近发现转录因子BCL11A是HBF开关和沉默的直接调节因子。通过全基因组关联研究，BCL11A最初被确定为HBF的候选调节因子。小鼠BCL11A基因敲除会损害成人红系细胞中发育中的HBF沉默。人源化SCD小鼠BCL11A的失活通过高水平的HBF诱导纠正了血液学和病理缺陷。因此，BCL11A代表了第一个在基因和功能上证实的人类HBF沉默的调节因子。为了进一步评估BCL11A作为一个可行的治疗靶点，重要的是要检查几个标准，包括BCL11A缺失对红细胞中非珠蛋白基因的影响以及对红系以外的影响。这项应用的目的是分析BCL11A在正常造血中的作用，并研究其特定细胞类型功能的分子机制。我假设BCL11A与不同的伙伴蛋白相互作用，并根据细胞环境针对不同的染色质区域。为了验证这一假设，我将：1，在条件基因敲除小鼠模型中确定BCL11A在正常造血过程中的作用；2，通过比较基因组和蛋白质组分析，确定BCL11A在红系和淋巴系细胞中以BCL11A为中心的转录网络。我期望这项研究的发现不仅将揭示疾病相关的造血调节因子介导的细胞类型特异性调控的一般特征，而且为设计针对BCL11A的治疗策略提供必要的基础，以诱导患有主要血红蛋白疾病的患者的HBF。

DESCRIPTION (provided by applicant): Analysis of the molecular mechanisms regulating human hemoglobin switching is critical to the development of target-based therapies for β-hemoglobin disorders, including sickle cell disease and β-thalassemias. Reactivation of fetal hemoglobin (HbF) in adults lessens the severity of these conditions. We recently showed that the transcription factor BCL11A is a direct regulator of HbF switching and silencing. BCL11A was initially identified as a candidate regulator of HbF through genome-wide association studies (GWAS). Knockout of BCL11A in mice impairs developmental HbF silencing in adult erythroid cells. Inactivation of BCL11A in humanized SCD mice corrects the hematologic and pathologic defects through high-level HbF induction. Thus, BCL11A represents the first genetically and functionally validated regulator of HbF silencing in man. To further evaluate BCL11A as a practicable therapeutic target, it is important to examine several criteria, including effects of BCL11A loss on non-globin genes in red cells and impact outside the erythroid lineage. The objective of this application is to analyze the role of BCL11A in normal hematopoiesis and investigate the molecular mechanisms underlying its cell-type- specific functions. I hypothesize that BCL11A interacts with different partner proteins and targets distinct chromatin regions depending on the cellular context. To test this hypothesis, I will : 1, Define the role of BCL11A during normal hematopoiesis in conditional knockout mouse models; and 2, Characterize BCL11A-centered transcriptional networks in erythroid and lymphoid cells by comparative genomic and proteomic analyses. I expect that findings from this study not only will reveal general features of cell- type-specific regulation mediated by a disease-associated hematopoietic regulator, but provide the necessary foundation for designing therapeutic strategies to target BCL11A for HbF induction in patients with the major hemoglobin disorders.