Prolactin gene expression dynamics and mammotrope function

催乳素基因表达动态和催乳素功能

• 批准号: 7614269
• 负责人: Fredric Ross Boockfor
• 金额: $ 29.33万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7614269
• 关键词: Address; Animals; Anterior Pituitary Gland; Binding; Binding Sites; Boxing; Cell physiology; Cells; Characteristics; Circadian Rhythms; Complex; Embryo; Endocrine; Female; Fertilization; Gene Expression; Gene Expression Regulation; Hypothalamic structure; Individual; Laboratories; Lactotrope Cell; Life; Light; Mammalian Cell; Manuscripts; Measurement; Microscopic; Molecular; Nature; Pattern; Physiologic pulse; Physiological; Pituitary Hormones; Population; Positioning Attribute; Pregnancy; Process; Proestrus; Prolactin; Rattus; Readiness; Regulation; Reproduction; Reproductive system; Role; Site; Techniques; Testing; Thyrotropin-Releasing Hormone; Time; Tissues; cell fixing; falls; implantation; insight; promoter; release factor; reproductive; reproductive function; research study; response; tool; transcription factor

DESCRIPTION (provided by applicant): Prolactin (PRL) is released by the anterior pituitary and is important for the proper functioning of a wide variety of tissues, especially those of the reproductive system. PRL is expressed with temporal characteristics that suggest a high degree of regulation. Much of this can be attributed to the number and type of hypothalamic factors that act on the mammotrope population to modulate its synthesis and release. However, an equally important consideration in understanding the process of PRL regulation is the functional state of the mammotropes on which these factors act. Our measurement of PRL gene expression (PRL-GE) in individual living mammotropes revealed that cells with lower basal levels of PRL-GE were more responsive to thyrotropin releasing hormone than cells with higher levels indicating that the state of a target cell greatly impacts its response. Moreover, recent experiments revealed that these basal levels of PRL-GE are not constant, but oscillate in repetitive bursts or pulses. These oscillations reflect temporal changes in basal activity that would likely dictate the readiness of the cell to respond to secretagogues. Finally, these PRL-GE pulses were found to depend on a specific site in the PRL promoter termed an E-box that bind transcription factors associated with circadian gene regulation suggesting that elaboration of a pulse is a highly regulated and specifically timed cellular process. Taken together, it is clear that an understanding of PRL-GE pulses is critical to fully comprehend the regulation of PRL and its impact on the reproductive system. In this study, we propose to test the hypothesis that "pulses of PRL-GE are fundamental to the control of both basal and stimulated mammotrope function and consequently are an important facet of normal reproductive function". This will be accomplished by addressing three SPECIFIC AIMS: I) to determine whether basal pulse patterns of PRL-GE and secretion in individual cells are fixed or change with varying reproductive state, II) to elucidate the relationship between pulses of PRL-GE and hypothalamic secretagogue action (i.e., stimulatory or inhibitory) in single mammotropes, and III) to identify the molecular processes that underlie pulsatile PRL- GE in mammotropes. Information gained from these studies will provide important insight into the role of this fundamental aspect of PRL expression and should contribute markedly to our understanding of the treatment of hyper or hypoprolactinemic conditions that impact reproduction.

描述（由申请人提供）：催乳素（PRL）由垂体前叶释放，对于多种组织（尤其是生殖系统组织）的正常运作非常重要。 PRL 的表达具有时间特征，表明存在高度调节。这在很大程度上可以归因于作用于促乳素群体以调节其合成和释放的下丘脑因子的数量和类型。然而，在理解 PRL 调节过程时，同样重要的考虑因素是这些因素作用的催乳素的功能状态。我们对个体活体催乳素中PRL基因表达（PRL-GE）的测量表明，基础PRL-GE水平较低的细胞比水平较高的细胞对促甲状腺素释放激素的反应更敏感，这表明靶细胞的状态极大地影响其反应。此外，最近的实验表明，PRL-GE 的这些基础水平不是恒定的，而是以重复的突发或脉冲形式振荡。这些振荡反映了基础活动的时间变化，这可能决定细胞对促分泌素做出反应的准备情况。最后，发现这些 PRL-GE 脉冲依赖于 PRL 启动子中称为 E-box 的特定位点，该位点结合与昼夜节律基因调节相关的转录因子，表明脉冲的形成是一个高度调控且特定定时的细胞过程。综上所述，很明显，了解 PRL-GE 脉冲对于充分理解 PRL 的调节及其对生殖系统的影响至关重要。在这项研究中，我们建议检验以下假设：“PRL-GE 脉冲对于控制基础和刺激的促乳腺功能至关重要，因此是正常生殖功能的一个重要方面”。这将通过解决三个具体目标来实现：I) 确定 PRL-GE 的基础脉冲模式和单个细胞的分泌是否是固定的或随着不同的生殖状态而变化，II) 阐明 PRL-GE 脉冲和单个催乳素中下丘脑促分泌作用（即刺激或抑制）之间的关系，以及 III) 识别脉冲背后的分子过程 促乳剂中的 PRL-GE。从这些研究中获得的信息将为了解 PRL 表达这一基本方面的作用提供重要的见解，并应显着有助于我们理解影响生殖的高催乳素血症或低催乳素血症的治疗。