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节提供了一个独特的窗口，在母体血液系统发生巨大变化的同时，胎儿发生了新生的造血发育。这项工作的一个中心假设是，这些造血变化部分是由胎盘产生的妊娠特异性因素引起的。不寻常的造血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控途径。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)，它们刺激小鼠巨核细胞分化，并与其他细胞因子协同刺激各种小鼠和人髓细胞前体的生长。PLP-E和PLP-F结合同一受体，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，以响应血小板水平低（血小板减少），并且给予这种激素可导致血小板减少症的恢复。本研究的目的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妊娠适应的新方面。本提案的具体目的是：(1)鉴定PLP-E和PLP-F受体；(2)确定与其他细胞因子反应不同的激素与受体结合如何导致信号事件和基因表达变化；(3)确定这些激素对体内造血的影响；(4)研究PLP-E基因在胎盘和骨髓中的调控机制。除了揭示妊娠期和疾病中造血控制的基本方面外，这些研究有望为治疗血小板减少症和其他造血疾病指明新的治疗方法。

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.