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

催乳素受体信号传导调节怀孕和产后心脏的适应

• 批准号: 10662892
• 负责人: Ronadip Ralph Banerjee
• 金额: $ 24.43万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-08 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662892
• 关键词: Acute; Adipose tissue; Adult; Adverse effects; Age; Biology; Birth; Breast Feeding; Cardiac; Cardiac Myocytes; Cardiovascular system; Categories; Classification; Clinical; Data; Development; Discipline of Nursing; Disease; Echocardiography; Endocrine; Ensure; Exercise; Failure; Female; Fetal Development; Fibrosis; Functional disorder; Gene Expression; Genetic; Goals; Grant; Growth; Health; Heart; Heart Diseases; Heart failure; Histologic; Homeostasis; Hormones; Human Milk; Individual; Isotopes; Lactation; LoxP-flanked allele; Mammary Gland Parenchyma; Mammary gland; Mediating; Metabolic; Metabolism; Modeling; Molecular; Mothers; Mus; Myocardial; Myocardium; National Institute of Child Health and Human Development; Nature; Nurses; Organ; Outcome; Pathologic; Pathway interactions; Performance; Physiological; Postpartum Period; Pregnancy; Pregnant Women; Process; Prolactin Receptor; Prolonged Lactations; Radiolabeled; Receptor Signaling; Research; Resolution; Role; Signal Transduction; Stimulus; Stress; Structure; Structure of beta Cell of islet; Testing; Tissues; Transcriptional Regulation; blood glucose regulation; cardioprotection; fetal; functional adaptation; heart function; improved; insight; insulin secretion; insulin signaling; lactation period; lactogenesis; lipid metabolism; meetings; milk production; mouse model; novel; peripartum cardiomyopathy; physiologic stressor; pressure; programs; protein expression; response; stressor

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.

心脏必须不断地适应多种刺激和压力源，这些刺激和压力源通常分为 病理和生理分类。其中，怀孕的生理压力及其后果 (i.e.,产后哺乳期和哺乳期）了解相对较少，而且还有很多未知之处 关于心外信号如何调节和协调这些过程。在一些不同的产妇 组织，包括乳腺、脂肪和胰腺β细胞、催乳激素，通过催乳素起作用 受体（PRLR），激活下游信号转导和转录调节机制， 协调妊娠期间的靶组织活动以及分娩和护理后的消退。到目前为止， 妊娠期间心脏中的PRLR信号尚未研究。该补助金的目的是建立一个 PRLR在心脏适应妊娠和产后妊娠变化逆转中的作用。 我们探讨了核心假设，即心肌细胞催乳信号，通过催乳素受体，是必不可少的心脏 适应。我们将在两个特定的细胞中研究心肌细胞催乳信号的新的生理作用。 目标。在目标1中，我们将建立心脏适应中对心肌细胞PRLR信号传导的需求 孕期同样，在目标2中，我们将确定心肌细胞PRLR信号在产后抑郁症中的作用。 在母亲哺乳期间，心脏的适应性妊娠变化逆转。到 为此，我们采用了一种新的和独特的遗传小鼠模型，该模型具有心肌细胞特异性PRLR缺失 （CM-PRLRKO小鼠）。我们使用多种分析来检查CM-PRLRKO小鼠，包括功能分析。 （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的心脏保护益处，例如缺乏 催乳素受体信号或未能护理和乳酸将对心脏功能和重塑产生不利影响。 这项研究意义重大，因为这些研究将是第一个建立PRLR的生理作用 在母体心脏的适应性反应中发出信号。在基础层面上，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，并可能确定新的途径，心脏恢复自己后，急性生理应激。