Characterizing the role of BCL11A in hematopoietic development and functions

描述（由申请人提供）：分析调节人类血红蛋白转换的分子机制对于开发针对β-血红蛋白疾病（包括镰状细胞病和β-地中海贫血）的靶向疗法至关重要。成人胎儿血红蛋白 (HbF) 的重新激活可减轻这些病症的严重程度。我们最近证明转录因子 BCL11A 是 HbF 转换和沉默的直接调节因子。通过全基因组关联研究 (GWAS)，BCL11A 最初被确定为 HbF 的候选调节因子。敲除小鼠中的 BCL11A 会损害成年红细胞中发育性 HbF 沉默。人源化 SCD 小鼠中 BCL11A 失活可通过高水平 HbF 诱导纠正血液学和病理学缺陷。因此，BCL11A 代表了第一个经过基因和功能验证的人类 HbF 沉默调节剂。为了进一步评估 BCL11A 作为可行的治疗靶点，重要的是检查几个标准，包括 BCL11A 丢失对红细胞中非珠蛋白基因的影响以及对红细胞谱系之外的影响。本应用的目的是分析 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 与不同的伙伴蛋白相互作用，并根据细胞环境靶向不同的染色质区域。为了检验这个假设，我将： 1、在条件敲除小鼠模型中定义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来表征红细胞和淋巴细胞中以 BCL11A 为中心的转录网络。我预计这项研究的结果不仅将揭示由疾病相关造血调节剂介导的细胞类型特异性调节的一般特征，而且为设计针对主要血红蛋白疾病患者的 BCL11A 诱导 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.