Prolactin receptor signaling regulates adaptation of the heart during pregnancy and postpartum

心脏必须不断地适应多种刺激和压力源，通常分为 病理学和生理学分类。其中，怀孕的生理应激及其后果 (即产后哺乳期和哺乳期)相对了解较少，也有许多未知 心脏外信号如何调节和协调这些过程。在许多不同的母体中 组织，包括乳腺、脂肪和胰腺β细胞，通过催乳素起作用的催乳素 受体(PRLR)，激活下游信号转导和转录调节机制，以 在怀孕期间协调目标组织活动，并在分娩和护理后恢复。到目前为止， 孕期心脏中的PRLR信号尚未被研究过。这笔赠款的目的是建立一个 PRLR在心脏适应妊娠和逆转产后妊娠变化中的作用。 我们探讨了一个中心假设，即心肌细胞通过PRLR产生的产乳信号对心脏功能是必不可少的。 适应。我们将研究心肌细胞产乳素信号在两个特定的 目标。在目标1中，我们将确定心脏适应中对心肌细胞PRLR信号的需求 在怀孕期间。同样，在目标2中，我们将确定心肌细胞PRLR信号在产后的作用 在母亲哺乳期间，心脏中适应性妊娠变化的逆转。至 为此，我们采用了一种新颖而独特的小鼠基因模型，该模型含有心肌细胞特异性的PRLR缺失 (CM-PRLRKO小鼠)。我们使用多种分析方法检查CM-PRLRKO小鼠，包括功能 (超声心动图)、分子(基因和蛋白质表达)、细胞(组织学)和代谢(放射性标记) 同位素示踪)研究。总之，这些研究将证明PRLR是正常妊娠所必需的。 心脏重塑，以及哺乳和母乳喂养对心脏保护的好处，如缺乏 PRLR信号的缺失或护理和乳酸的失败将对心脏功能和重塑产生不利影响。 这项研究意义重大，因为这些研究将第一次确立PRLR的生理作用 母体心脏适应性反应中的信号转导。从根本上说，这些研究将扩大 我们对激素调节心肌细胞的背景和分子机制的理解 功能，并可能确定心脏在急性生理应激后恢复自身的新途径。

The heart must continually adapt to a multitude of stimuli and stressors, which are generally divided into pathologic and physiologic categories. Amongst these, the physiologic stress of pregnancy and its aftermath (i.e., the postpartum period of lactation and nursing) are relatively less well understood, and much is unknown about how extra-cardiac signals regulate and coordinate these processes. In a number of diverse maternal tissues, including mammary glands, adipose and pancreatic β-cells, lactogenic hormones, acting via the prolactin receptor (PRLR), activate downstream signal transduction and transcriptional regulation machinery to orchestrate target tissue activity during pregnancy and regression following parturition and nursing. To date, PRLR signaling in the heart during pregnancy has not been studied. The objective of this grant is to establish a role for PRLR in adaptation of the heart to pregnancy and the reversal of gestational changes in the postpartum. We explore the central hypothesis that cardiomyocyte lactogenic signaling, via PRLR, is essential for cardiac adaptation. We will investigate novel physiologic roles of cardiomyocyte lactogenic signaling in two Specific Aims. In Aim 1, we will establish the requirement for cardiomyocyte PRLR signaling in the adaptation of the heart during pregnancy. Similarly, in Aim 2, we will identify a role of cardiomyocyte PRLR signaling in the postpartum reversal of adaptive gestational changes in the heart, during the nursing period when the mother is lactating. To do so, we employ a novel and unique genetic mouse model harboring a cardiomyocyte-specific deletion of PRLR (CM-PRLRKO mice). We examine CM-PRLRKO mice using multiple analyses, including functional (echocardiography), molecular (gene and protein expression), cellular (histologic), and metabolic (radiolabeled isotope tracing) studies. Together, these studies will demonstrate that PRLR is required for normal gestational cardiac remodeling, as well as for the cardioprotective benefits of lactation and breastfeeding, such that absence of PRLR signaling or failure to nurse and lactate will have adverse effects on cardiac function and remodeling. This research is significant because these studies would be the first to establish a physiologic role for PRLR signaling in the adaptive responses of the maternal heart. At a fundamental level, these studies would expand our understanding of the context and molecular mechanisms by which hormones regulate cardiomyocyte function, and may identify novel pathways by which the heart restores itself following acute physiologic stressors.