Placental hormones and the control of hematopoiesis

描述(申请人提供)：哺乳动物怀孕为造血调控提供了一个独特的窗口，母体血液系统在发生巨大变化的同时，胎儿发生了从头开始的造血发育。这项工作的一个中心假设是，这些造血变化在一定程度上是由胎盘产生的妊娠特有因素引起的。异常的造血模式可能反映了新的活动，在这种情况下，对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)和催乳素样蛋白F(PLP-F)，它们能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系前体细胞的生长。PLP-E和PLP-F与相同的受体结合，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，以应对低血小板水平(血小板减少症)，而这种激素的应用会导致血小板减少症的恢复。这项建议的目的是扩大我们对这两种激素是如何表达和如何作用的理解，并通过这些研究揭示控制造血和适应怀孕的新方面。这项建议的具体目的是：(1)鉴定PLP-E和PLP-F受体；(2)确定激素与受体结合如何导致信号事件和不同于对其他细胞因子的反应的基因表达变化；(3)确定这些激素对体内造血的影响；以及(4)表征PLP-E基因在胎盘和骨髓中的调控方式。除了揭示妊娠和疾病中造血控制的基本方面外，这些研究有望指出治疗血小板减少症和其他造血疾病的新治疗方法。

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.