Prolactin Feedback to Hypothalamic Dopaminergic Neurons

催乳素对下丘脑多巴胺能神经元的反馈

• 批准号: 7368087
• 负责人: LYDIA A ARBOGAST
• 金额: $ 33.22万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7368087
• 关键词: Acute; Affect; Anabolism; Animals; Back; Cell Line; Cells; Cultured Cells; Cytokine Inducible SH2-Containing Protein; Defect; Dopamine; Elevation; Enzymes; Feedback; Feeds; Fertility; Gene Expression; Genes; Genetic Transcription; Hormonal; Human Milk; Hyperprolactinemia; Hypothalamic structure; Immunoprecipitation; In Situ Hybridization; In Vitro; Infertility; Janus kinase 2; Lactation; MAP2K1 gene; MEKs; Maintenance; Messenger RNA; Modeling; Molecular; Neuraxis; Neurons; Neurosecretory Systems; Newborn Infant; Numbers; Pathway interactions; Phosphorylation; Phosphotransferases; Pituitary Gland; Play; Post-Translational Protein Processing; Process; Prolactin; Prolactin Receptor; Prolactin Release-Inhibiting Hormone; Protein Dephosphorylation; Ras/Raf; Rate; Rattus; Reporter; Role; STAT protein; Signal Pathway; Signal Transduction; Signaling Protein; System; Techniques; Time; Tyrosine 3-Monooxygenase; Tyrosine Kinase Inhibitor; Tyrosine Phosphorylation; Western Blotting; Woman; dopaminergic neuron; extracellular; immunocytochemistry; in vivo; inhibitor/antagonist; men; ovex (pesticide); promoter; reproductive function; reproductive success; research study; response; transcription factor; tumor

DESCRIPTION (provided by applicant): Prolactin is absolutely essential for normal lactation and breast milk is considered the optimal nourishment for newborn infants. As part of its role in maintaining the maternal process, prolactin has multiple and important effects within the central nervous system. Although prolactin is critical for some aspects of reproductive success, too much prolactin is detrimental for fertility. Prolactin-secreting tumors are the most prevalent pituitary defect and the resulting hyperprolactinemia causes infertility in men and women. The tuberoinfundibular dopaminergic neurons in the hypothalamus provide the major neuroendocrine control to maintain circulating prolactin levels low, but sufficient, for normal reproductive function. Dopamine acts as the major prolactin-inhibiting factor and prolactin, in turn, feeds back to increase dopaminergic neuronal activity, Tyrosine hydroxylase is the rate-limiting enzyme in dopamine biosynthesis and its activity is highly regulated at the level of transcription of the tyrosine hydroxylase gene and by post-translational control mechanisms such as phosphorylation/dephosphorylation of the existing enzyme. Yet, we know very little about how hypothalamic dopaminergic neurons integrate the prolactin-induced signals to enhance neuronal activity. The proposed studies will utilize several models to elucidate mechanisms involved in prolactin control of tyrosine hydroxylase in hypothalamic dopaminergic neurons. Intact animals will be used to determine the integrative effects of prolactin when all hypothalamic and extrahypothalamic inputs are intact. Primary hypothalamic cell cultures will be used to isolate dopaminergic neurons from extrahypothalamic inputs. Neuronal cell lines will be used to fully explore cellular and molecular mechanisms. Experiments will examine contributions of gene expression and post-translational modifications to increase dopaminergic neuronal function. The expression and phosphorylation/ activation of acute and prolonged prolactin-induced signals within the hypothalamus and specifically within dopaminergic neurons will be analyzed. The roles of these prolactin activated signaling pathways to initiate or sustain the increase in tyrosine hydroxylase activity will be examined. The last set of experiments will evaluate molecular mechanisms that contribute to prolactin enhancement of tyrosine hydroxylase gene expression. Critical new information on prolactin's actions within the central nervous system should result from the proposed experiments.

描述（由申请人提供）：催乳素对正常泌乳是绝对必要的，母乳被认为是新生儿的最佳营养。作为其在维持母体过程中的作用的一部分，催乳素在中枢神经系统内具有多种重要作用。虽然催乳素对生殖成功的某些方面至关重要，但过多的催乳素对生育不利。催乳素分泌肿瘤是最常见的垂体缺陷，由此产生的高催乳素血症会导致男性和女性不孕。下丘脑中的结节漏斗多巴胺能神经元提供主要的神经内分泌控制，以维持循环催乳素水平较低，但足以维持正常的生殖功能。多巴胺作为主要的催乳素抑制因子，而催乳素反过来又反馈增加多巴胺能神经元活性。酪氨酸羟化酶是多巴胺生物合成中的限速酶，其活性在酪氨酸羟化酶基因的转录水平和翻译后控制机制（如现有酶的磷酸化/去磷酸化）高度调节。然而，我们对下丘脑多巴胺能神经元如何整合催乳素诱导的信号以增强神经元活性知之甚少。拟开展的研究将利用几种模型来阐明催乳素控制下丘脑多巴胺能神经元酪氨酸羟化酶的机制。当所有下丘脑和下丘脑外输入完整时，将使用完整动物确定催乳素的整合效应。原代下丘脑细胞培养物将用于从下丘脑外输入中分离多巴胺能神经元。神经元细胞系将用于充分探索细胞和分子机制。实验将研究基因表达和翻译后修饰对增加多巴胺能神经元功能的贡献。将分析下丘脑内，特别是多巴胺能神经元内的急性和长期催乳素诱导信号的表达和磷酸化/活化。这些催乳素激活的信号通路的作用，启动或维持酪氨酸羟化酶活性的增加将进行检查。最后一组实验将评估分子机制，有助于催乳素增强酪氨酸羟化酶基因的表达。催乳素在中枢神经系统中的作用的关键新信息应该来自拟议的实验。