Placental hormones and the control of hematopoiesis

胎盘激素和造血控制

• 批准号: 6687797
• 负责人: DANIEL I LINZER
• 金额: $ 32.83万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6687797
• 关键词: biological signal transduction; bone marrow; cell line; cytokine; cytokine receptors; gel mobility shift assay; gene expression; genetic library; genetic transcription; genetically modified animals; hematopoiesis; hormone regulation /control mechanism; in situ hybridization; laboratory mouse; placental hormones; polymerase chain reaction; pregnancy; receptor binding; transfection; trophoblast

DESCRIPTION (provided by applicant): Mammalian pregnancy provides a unique window on the regulation of hematopoiesis, with massive changes in the maternal blood system at the same time that de novo hematopoietic development occurs in the fetus. A central hypothesis of this work is that these hematopoietic changes are induced in part by pregnancy-specific factors produced by the placenta. The unusual patterns of hematopoiesis may reflect novel activities, in which case analysis of placental hematopoietic hormones will reveal new regulatory pathways. Placental hormones in the cytokine superfamily in the mouse include prolactin-like proteins E (PLP-E) and F (PLP-F) which stimulate mouse megakaryocyte differentiation and synergize with other cytokines to stimulate the growth of various mouse and human myeloid precursors. PLP-E and PLP-F bind to the same receptor, which does not appear to be shared with other cytokines. PLP-E, but not PLP-F, is also expressed in the mouse bone marrow in response to low platelet levels (thrombocytopenia), and administration of this hormone leads to recovery from thrombocytopenia. The goals of this proposal are to expand our understanding of how these two hormones are expressed and how they act, and through these studies to reveal new aspects of the control of hematopoiesis and the adaptation to pregnancy. The Specific Aims of this proposal are: (1) to identify the PLP-E and PLP-F receptor; (2) to determine how hormone binding to receptor leads to signaling events and to changes in gene expression that are distinct from the responses to other cytokines; (3) to define the effects these hormones have on hematopoiesis in vivo; and (4) to characterize how the PLP-E gene is controlled in the placenta and the bone marrow. In addition to revealing basic aspects of the control of hematopoiesis in pregnancy and in disease, these studies are expected to point to new therapeutic approaches in the treatment of thrombocytopenia and other hematopoietic disorders.

描述（由申请人提供）：哺乳动物妊娠提供了一个独特的造血调节窗口，同时胎儿造血系统发生的同时，孕产妇血液系统发生了巨大变化。这项工作的一个核心假设是，这些造血变化是由胎盘产生的妊娠特异性因素所诱导的。造血的异常模式可能反映出新的活性，在这种情况下，胎盘造血激素的分析将揭示新的调节途径。小鼠细胞因子超家族中的胎盘激素包括催乳素样蛋白E（PLP-E）和F（PLP-F），这些蛋白质E（PLP-E）刺激小鼠巨核细胞分化，并与其他细胞因子协同以刺激各种小鼠和人髓样前体的生长。 PLP-E和PLP-F与同一受体结合，似乎与其他细胞因子共享。 PLP-E（而不是PLP-F）也在小鼠骨髓中表达，响应低血小板水平（血小板减少症），并且该激素的给药会导致从血小板减少症中恢复。 该提案的目标是扩展我们对这两种激素如何表达以及它们的作用以及通过这些研究的理解，以揭示造血控制的新方面和对怀孕的适应。该提案的具体目的是：（1）识别PLP-E和PLP-F受体； （2）确定激素与受体的结合如何导致信号事件以及与其他细胞因子反应不同的基因表达的变化； （3）定义这些激素对体内造血的影响； （4）为如何在胎盘和骨髓中控制PLP-E基因。除了揭示妊娠和疾病中造血性控制的基本方面外，这些研究还应指出治疗血小板减少症和其他造血疾病的新治疗方法。