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

基本信息

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
项目类别：
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

项目摘要

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.

心脏必须不断适应多种刺激和压力源，通常分为其中，妊娠的生理应激及其后果。（即产后哺乳期）相对不太了解，而且很多都是未知的关于心脏外信号如何在许多不同的母亲中调节和协调这些过程。组织，包括乳腺、脂肪和胰腺 β 细胞、通过催乳素发挥作用的催乳激素受体（PRLR），激活下游信号转导和转录调节机制协调怀孕期间的目标组织活动以及分娩和哺乳后的退化。怀孕期间心脏中的 PRLR 信号传导尚未得到研究。这项资助的目的是建立一个机制。 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 产生的泌乳信号传导对于心脏功能至关重要。我们将研究心肌细胞泌乳信号传导在两种特定情况下的新生理作用。在目标 1 中，我们将确定心肌细胞 PRLR 信号传导在心脏适应中的要求。同样，在目标 2 中，我们将确定心肌细胞 PRLR 信号传导在产后的作用。在母亲哺乳期的哺乳期间，逆转心脏的适应性妊娠变化。为此，我们采用了一种新颖且独特的遗传小鼠模型，该模型含有心肌细胞特异性 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）同位素追踪）研究共同证明 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的保护作用，例如缺乏 PRLR 信号传导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，因为这些研究将是第一个确定 PRLR 的生理作用的研究从根本上讲，这些研究将扩大母体心脏适应性反应的信号传导。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源后恢复自身的新途径。