Molecular Events Initiating B Cell Fate Determination

启动 B 细胞命运决定的分子事件

• 批准号: 7799155
• 负责人: Kay Lynn Medina
• 金额: $ 37.78万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-06 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7799155
• 关键词: Animals; Antibodies; B cell differentiation; B-Cell Development; B-Lymphocytes; Blood; Blood Cells; Bone Marrow; Cell Line; Cell Proliferation; Cell model; Commit; Data; Defect; Development; Disease; Dose; Down-Regulation; Event; Gene Expression; Gene Expression Profiling; Gene Targeting; Generations; Genes; Goals; Hematological Disease; Hematopoietic; Hematopoietic stem cells; Homeostasis; HoxA protein; Immune system; Immunodeficiency and Cancer; Immunologic Deficiency Syndromes; Infection; Intervention; Knowledge; Learning; Leukocytes; Life; Ligands; Link; Lymphoid; Lymphopoiesis; Mediating; Microarray Analysis; Molecular; Molecular Target; Mus; Pathway interactions; Pattern; Play; Process; Production; Proteins; Rag1 Mouse; Receptor Protein-Tyrosine Kinases; Regulation; Regulator Genes; Reporter; Research Design; Role; Series; Signal Transduction; Stem cells; TCF3 gene; Testing; Transcript; animal data; base; cytokine; design; fighting; functional genomics; helix-loop-helix protein differentiation inhibitor; humoral immunity deficiency; insight; interest; leukemia; novel; overexpression; progenitor; protein B; public health relevance; research study; stem cell biology; transcription factor

DESCRIPTION (provided by applicant): B lymphocytes are critical blood cells and altered production or function can cause significant disease. We are interested in understanding how blood stem cells initiate B cell development. Delineating the normal B cell developmental pathway will provide insight into the molecular and cellular basis of many hematologic diseases. Although considerable progress has been made in understanding the generation of naive B cells from committed B cell precursors, little is known about how this process begins. This project will exploit exciting new findings concerning an unexpected regulatory connection between the receptor tyrosine kinase Flt3, HoxA proteins, and the B cell fate determinant EBF. Our new data suggest that this regulatory connection plays an important role in regulating the stem cell to Pro-B transition, and hence, the numbers of B lymphocytes generated. Specifically, we will learn how Flt3 signaling initiates a series of events, gradually biasing multipotential progenitors in bone marrow into the B lineage. Exciting new data revealed that Flt3 signaling, in a ligand-dose dependent fashion, regulates the activity of the primary B cell fate determinant, E2A, a key regulator of the EBF gene. Once expressed, EBF orchestrates B cell differentiation. Gene expression profiling of an EBF-/- cell line pointed to novel role for EBF during B cell development, namely controlling expression of a developmentally regulated cluster of HoxA proteins. Elucidating regulatory circuits that control HoxA expression is important, as dysregulated expression impairs B cell differentiation. First we will determine the molecular events between Flt3 signaling and EBF expression. Then we will determine the regulatory connection between EBF, HoxA, and Flt3 that controls the production of B lymphocytes. Overall, these experiments will provide basic knowledge of a vital process, the production of white blood cells that make antibodies to fight infections. The information should help identify molecular targets for intervention in blood cell cancers and immunodeficiency diseases. PUBLIC HEALTH RELEVANCE: During blood cell development, the stem cell to Pro-B transition is a pivotal checkpoint that controls B cell homeostasis. This project focuses on determining the molecular circuitry through which three critical factors, the receptor tyrosine kinase Flt3, HoxA proteins, and the B cell fate determinant EBF, orchestrate this critical checkpoint.

描述（由申请人提供）：B 淋巴细胞是关键的血细胞，其产生或功能的改变可能导致严重的疾病。我们有兴趣了解血液干细胞如何启动 B 细胞发育。描绘正常 B 细胞发育途径将有助于深入了解许多血液疾病的分子和细胞基础。尽管在了解从定型 B 细胞前体生成初始 B 细胞方面已经取得了相当大的进展，但对于这一过程是如何开始的却知之甚少。该项目将利用有关受体酪氨酸激酶 Flt3、HoxA 蛋白和 B 细胞命运决定因子 EBF 之间意想不到的调节联系的令人兴奋的新发现。我们的新数据表明，这种调节连接在调节干细胞向 Pro-B 转变以及由此产生的 B 淋巴细胞数量方面发挥着重要作用。具体来说，我们将了解 Flt3 信号传导如何启动一系列事件，逐渐将骨髓中的多能祖细胞偏向 B 谱系。令人兴奋的新数据表明，Flt3 信号传导以配体剂量依赖性方式调节初级 B 细胞命运决定因子 E2A（EBF 基因的关键调节因子）的活性。一旦表达，EBF 就会协调 B 细胞分化。 EBF-/- 细胞系的基因表达谱指出了 EBF 在 B 细胞发育过程中的新作用，即控制发育调控的 HoxA 蛋白簇的表达。阐明控制 HoxA 表达的调节回路非常重要，因为表达失调会损害 B 细胞分化。首先，我们将确定 Flt3 信号传导和 EBF 表达之间的分子事件。然后我们将确定 EBF、HoxA 和 Flt3 之间控制 B 淋巴细胞产生的调节联系。总的来说，这些实验将提供一个重要过程的基础知识，即白细胞的产生，从而产生抗体来对抗感染。这些信息应有助于确定干预血细胞癌和免疫缺陷疾病的分子靶点。公共卫生相关性：在血细胞发育过程中，干细胞向 Pro-B 的转变是控制 B 细胞稳态的关键检查点。该项目的重点是确定三个关键因素（受体酪氨酸激酶 Flt3、HoxA 蛋白和 B 细胞命运决定因子 EBF）协调这一关键检查点的分子回路。