Characterizing the role of BCL11A in hematopoietic development and functions

描述（由申请人提供）：分析调节人血红蛋白转换的分子机制对于开发β-血红蛋白疾病（包括镰状细胞病和β-地中海贫血）的靶向治疗至关重要。成人胎儿血红蛋白（HbF）的再激活可减轻这些疾病的严重程度。我们最近发现转录因子BCL11A是HbF转换和沉默的直接调节剂。BCL11A最初是通过全基因组关联研究（GWAS）确定为HbF的候选调节因子。敲除小鼠BCL11A可损害成年红细胞中HbF的发育沉默。在人源化SCD小鼠中，BCL11A的失活通过高水平HbF诱导纠正血液学和病理缺陷。因此，BCL11A代表了人类HbF沉默的第一个基因和功能验证的调节因子。为了进一步评估BCL11A作为一种可行的治疗靶点，重要的是要检查几个标准，包括BCL11A缺失对红细胞非珠蛋白基因的影响以及红细胞系外的影响。本应用程序的目的是分析BCL11A在正常造血中的作用，并研究其细胞类型特异性功能的分子机制。我假设BCL11A与不同的伴侣蛋白相互作用，并根据细胞环境靶向不同的染色质区域。为了验证这一假设，我将：1，在条件敲除小鼠模型中确定BCL11A在正常造血过程中的作用；2、通过比较基因组学和蛋白质组学分析，表征红细胞和淋巴细胞中以bcl11a为中心的转录网络。我希望本研究的发现不仅能揭示疾病相关造血调节因子介导的细胞类型特异性调节的一般特征，而且能为设计针对BCL11A诱导主要血红蛋白疾病患者HbF的治疗策略提供必要的基础。

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.