Characterizing the role of BCL11A in hematopoietic development and functions

表征 BCL11A 在造血发育和功能中的作用

• 批准号: 8679360
• 负责人: Jian Xu
• 金额: $ 5.35万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2014-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8679360
• 关键词: Adult; BCL11A gene; Biological Assay; Cell Lineage; Chromatin; Clinical; Defect; Dependence; Development; Disease; Dose; Down-Regulation; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Fetal Hemoglobin; Foundations; Gene Targeting; Genes; Genomics; Globin; Goals; Grant; Health; Hematopoiesis; Hematopoietic; Hemoglobin; Hemoglobinopathies; Human; Knock-out; Knockout Mice; Lymphoid Cell; Lymphopoiesis; Mediating; Mediator of activation protein; Molecular; Molecular Analysis; Mus; Pathogenesis; Pathologic; Patients; Production; Proteins; Proteomics; Regulation; Repressor Proteins; Research; Role; Severities; Sickle Cell Anemia; Stem cells; Syndrome; Testing; Thalassemia; Therapeutic; Transplantation; Zinc Fingers; base; cell type; comparative genomics; design; fetal; genome wide association study; improved; insight; man; mouse model; programs; stem; therapeutic target; transcription factor

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.

描述（由申请方提供）：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。胎儿血红蛋白（HbF）在成人中的重新激活减轻了这些疾病的严重程度。我们最近发现，转录因子BCL 11 A是HbF转换和沉默的直接调节因子。BCL 11 A最初通过全基因组关联研究（GWAS）被鉴定为HbF的候选调节因子。小鼠中BCL 11 A的敲除损害成年红系细胞中发育性HbF沉默。人源化SCD小鼠中BCL 11 A的失活通过高水平HbF诱导纠正血液学和病理学缺陷。因此，BCL 11 A代表了第一个基因和功能验证的调节HbF沉默在man. To进一步评估BCL 11 A作为一个可行的治疗靶点，重要的是要检查几个标准，包括BCL 11 A的损失对红细胞中的非珠蛋白基因的影响和红细胞系外的影响。本申请的目的是分析BCL 11 A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BCL 11 A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，定义BCL 11 A在条件性基因敲除小鼠模型中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系和淋巴细胞中以BCL 11 A为中心的转录网络。我期望来自本研究的发现不仅将揭示由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，而且为设计治疗策略以靶向BCL 11 A用于在患有主要血红蛋白疾病的患者中诱导HbF提供必要的基础。