Intrinsic and extrinsic control of erythropoietic maturation

红细胞生成成熟的内在和外在控制

• 批准号: 8714505
• 负责人: JAMES J BIEKER
• 金额: $ 35.66万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714505
• 关键词: Address; Adhesives; Adult; Affect; Biological Assay; Cell Adhesion Molecules; Cell Communication; Cell Line; Cell Maturation; Cell Nucleus; Cell Surface Proteins; Cells; Chromatin; Clinical; Complement; Congenital dyserythropoietic anemia; Defect; Deoxyribonucleases; Development; Differentiation and Growth; Epigenetic Process; Erythroblasts; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Evaluation; Event; Exhibits; Fetal Liver; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genetic Transcription; Globin; HDAC2 gene; Health; Hepatocyte; Human; Integrins; Iron; Island; Kupffer Cells; Lead; Maps; Mus; Myelogenous; Nuclear; Null Lymphocytes; Patients; Pattern; Peptides; Phenotype; Physical condensation; Play; Process; Pronormoblasts; Regulation; Research; Reticulocytes; Role; Signal Transduction; Source; Staging; Structure; System; Testing; Zinc Fingers; base; cell type; cytokine; design; embryonic stem cell; erythroid Kruppel-like factor; human GATA1 protein; in vivo; macrophage; mutant; peripheral blood; progenitor; research study; three dimensional structure; transcription factor

DESCRIPTION (provided by applicant): The terminal differentiation events of erythropoiesis do not occur in isolation, but rather within a specialized niche known as the erythroblastic island Adhesive macrophage-erythroid cell interactions are important for its integrity, which efficiently aid the red cell maturation progression from erythroblast to enucleated reticulocyte. Expression of specific adhesion molecules and nuclear condensation effectors each are critical for this process. However, how expression of the genes encoding these molecules is coordinated is not established. EKLF/KLF1 (erythroid Kr¿ppel-like factor) plays a global role in erythropoiesis by integrating transcriptional and epigenetic signals at specific loci. As a result, it merits consideration for performing such a role at late stages of differentiation. Such a conjecture is supported by experiments in differentiating murine embryonic stem cells, identification of relevant EKLF targets, its early and localized expression during development, deficiencies exhibited by EKLF-null fetal liver cells, the surprising expansion of EKLF expression pattern, and the red cell phenotype in a subset of congenital dyserythropoietic anemia patients. These form the basis for the following aims: 1-Investigate the role of EKLF in erythroblastic island formation and integrity during early development and in the adult 2-Elaborate on EKLF's unexpected role in the island macrophage 3-Utilize a proliferation/differentiation system of primary erythroid cells to address EKLF's ability to coordinate nuclear maturation events. This proposal is designed to test the hypothesis that EKLF plays a coordinating role in two processes that are intimately interconnected within the context of the erythroblastic island niche: adhesive erythroid-macrophage/cell-cell interactions, and enucleation of the red cell. Our studies build on observations made in primary or minimally manipulated cells that will be aided by in vivo assays and EKLF rescue systems. Our proposed experiments raise and will address the exciting idea that EKLF not only plays an intrinsic role in establishing the proper gene expression patterns in the red cell within the erythroblastic island, but that it additionally affects this process by an extrinsic mechanism based on its unanticipated expression within the island macrophage. Understanding these basic mechanisms will ultimately aid in the design of culture systems that enable efficient expansion and enucleation of human cell sources for clinical use.

描述（由适用提供）：红细胞生成的终末分化事件不是孤立的，而是在被称为红细胞岛粘附性巨噬细胞 - 刺激性细胞相互作用的专业生态市场中对其完整性很重要，这对其完整性很重要，这有效地有助于从成熟的红细胞成熟到卵形细胞的成熟。特定的粘合分子和核冷凝效应子的表达对于此过程至关重要。但是，未建立编码这些分子的基因的表达如何建立。 EKLF/KLF1（类红花样因子）通过在特定基因座的转录和表观遗传信号整合，在红细胞生成中起着全球作用。结果，它值得考虑在分化后期阶段扮演这样的角色。这种猜想是通过在区分鼠类胚胎干细胞中的实验，相关的EKLF靶标的实验来支持的，其在发育过程中的早期和局部表达，EKLF无效的胎儿肝细胞暴露的不足，EKLF表达模式的令人惊讶的扩展以及EKLF表达模式的扩张以及粘液性二氧化性菌株的红细胞表型以及红细胞表型。这些构成了以下目的的基础：1-Invest，在早期发展过程中EKLF在红细胞生成岛形成和完整性中的作用，以及成人2-塑造EKLF在岛屿巨噬细胞中的意外作用3-利用了eklf核能核能事件能力的主要红细胞的增殖/差异化系统。该提案旨在检验以下假设：EKLF在两个在红细胞岛壁che的背景下紧密相互联系的过程中起着坐标的作用：粘合剂 红细胞的红细胞相互作用和红细胞的启用。我们的研究以 在原始或微小操纵细胞中进行的观察结果将通过体内测定和EKLF救援系统有助于。我们提出的实验提出了一个令人兴奋的想法，即EKLF不仅在促成红细胞岛内红细胞中建立适当的基因表达模式中起着内在作用 基于其在岛上巨噬细胞中意外表达的外部机制。了解这些基本机制将最终有助于设计培养系统，从而有效地扩展和促进人类细胞来源进行临床使用。