Placental hormones and the control of hematopoiesis

描述（由申请人提供）：哺乳动物妊娠为造血调控提供了一个独特的窗口，在胎儿发生新生造血发育的同时，母体血液系统发生了巨大变化。这项工作的中心假设是，这些造血变化部分是由胎盘产生的妊娠特异性因子诱导的。造血的不寻常的模式可能反映了新的活动，在这种情况下，胎盘造血激素的分析将揭示新的调节途径。小鼠中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），其刺激小鼠巨核细胞分化并与其它细胞因子协同作用以刺激各种小鼠和人骨髓前体的生长。PLP-E和PLP-F与相同的受体结合，这似乎不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，以响应低血小板水平（血小板减少症），并且给予这种激素导致从血小板减少症中恢复。 该提案的目标是扩大我们对这两种激素如何表达及其作用的理解，并通过这些研究揭示造血控制和适应妊娠的新方面。本发明的具体目的是：（1）鉴定PLP-E和PLP-F受体;（2）确定激素与受体的结合如何导致信号传导事件和基因表达的变化，这与对其他细胞因子的反应不同;（3）确定这些激素对体内造血的影响;和（4）表征PLP-E基因在胎盘和骨髓中是如何被控制的。除了揭示妊娠和疾病中造血控制的基本方面外，这些研究还有望指出治疗血小板减少症和其他造血系统疾病的新治疗方法。

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.