Tropic Roles for Leptin in the Maturation of Somatotropes

瘦素在生长激素成熟中的热带作用

• 批准号: 9912144
• 负责人: GWEN V CHILDS
• 金额: $ 44.43万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912144
• 关键词: Ablation; Address; Adult; Age; Animal Model; Animals; Anterior Pituitary Gland; Attenuated; Binding; Binding Sites; Body Composition; Cell Lineage; Cells; Cessation of life; Child; Cognition Disorders; Data; Dependence; Desire for food; Development; Event; Exons; Female; Functional disorder; Genes; Genetic Transcription; Goals; Growth; Health; Heart Diseases; Homeostasis; Hypothalamic structure; Knock-out; Knockout Mice; Knowledge; Lactotrope Cell; Lead; Leptin; Leptin deficiency; Link; Maintenance; Malignant Neoplasms; Malnutrition; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic dysfunction; Methodology; MicroRNAs; Mission; Modeling; Mutant Strains Mice; Neonatal; Neuroglia; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathway interactions; Perinatal; Physiological; Pituitary Gland; Play; Population; Prevention; Prolactin; Proteins; Public Health; Regulation; Regulatory Pathway; Reporting; Repression; Research; Role; Signal Pathway; Signal Transduction; Somatotrope Cell; Somatotropin; Somatotropin-Releasing Hormone; Source; Specific qualifier value; Testing; Therapeutic; Thyroid Gland; Thyrotropin; Translations; United States National Institutes of Health; Untranslated Regions; Work; adipokines; base; burden of illness; cell type; critical period; design; innovation; insight; leptin receptor; novel; novel diagnostics; novel therapeutic intervention; perinatal development; prevent; programs; sensor; sex; targeted treatment; transcription factor

PROJECT SUMMARY/ABSTRACT Metabolic health is critically dependent on tropic actions by the adipokine leptin, which programs the hypothalamus during perinatal development to receive normal metabolic signals. Anterior pituitary somatotropes are dependent on leptin for normal metabolic functions, however, the developmental timing of this leptin dependency and underlying mechanisms represent a gap in our knowledge of leptin's broader roles. The overall objective of this application is to ascertain the importance of the neonatal surge of leptin to somatotrope maturation. Our first hypothesis states that normal somatotrope maturation is dependent on perinatal leptin signals and that lack of early leptin signals alters adult somatotrope functions. Our second hypothesis states that leptin regulates somatotropes through effector pathways involving the POU1F1/PIT1 transcription factor, the mRNA translational control protein, Musashi (MSI) and regulatory microRNAs (miRNAs). Two aims will test these hypotheses: Aim 1 studies will determine how the loss of leptin signals impacts neonatal maturation of somatotropes and their metabolic functions in the adult. We will study the neonatal development of somatotropes in animal models in which leptin signals are either: 1) deleted following the somatotrope- selective ablation of Lepr exon 1; 2) blocked by a leptin antagonist during the leptin surge or 3) attenuated by maternal undernutrition. We will replace neonatal leptin in the undernourished animals to test the hypothesis that early leptin signaling is vital for neonatal maturation of somatotropes and their normal function in the adult. Aim 2 studies will identify mechanisms underlying the leptin regulation of somatotropes. These studies will use purified populations of somatotropes to determine if leptin's actions are mediated by signaling pathways that attenuate MSI-mediated repression of Pou1f1, Tsh, and Prl mRNAs. We will also study miRNA-mediated repression of Gh and Ghrhr mRNAs and will employ unbiased approaches to identify additional novel leptin-dependent mechanisms controlling somatotrope maturation. This contribution is significant because it addresses the global problem of the importance of leptin in the prevention of the metabolic dysfunction caused by maternal undernutrition, which contributes to 11% of the total global disease burden, ultimately leading to 35% of child deaths. The proposed research is conceptually innovative because it broadens our understanding of leptin actions to include cells in the anterior pituitary that are known to be important metabolic sensors, and introduces novel regulatory pathways for leptin and utilizes methodological advancements in the purification of somatotropes. The expected outcomes of the work are that (1) the findings will fully inform the field about leptin's tropic role in somatotrope maturation and function and (2) this work will provide information about mechanisms of leptin's action that may be targeted therapeutically to prevent the severe metabolic dysfunction caused by early leptin deficiency.

项目概要/摘要 代谢健康严重依赖于脂肪因子瘦素的热带作用，它对 下丘脑在围产期发育期间接收正常的代谢信号。垂体前叶 生长激素的正常代谢功能依赖于瘦素，但是，生长激素的发育时间 这种瘦素依赖性和潜在机制代表了我们对瘦素更广泛作用的认识上的差距。 本申请的总体目标是确定新生儿瘦素激增对 生长激素成熟。我们的第一个假设指出，正常的生长素成熟取决于 围产期瘦素信号的影响以及早期瘦素信号的缺乏会改变成年生长激素 功能。我们的第二个假设指出瘦素通过效应器调节生长激素 涉及 POU1F1/PIT1 转录因子（mRNA 翻译控制）的通路 蛋白质、Musashi (MSI) 和调节性 microRNA (miRNA)。有两个目标将检验这些假设： 目标 1 研究将确定瘦素信号的丢失如何影响新生儿的成熟 生长激素及其在成人中的代谢功能。我们将研究新生儿的发育 动物模型中的生长激素，其中瘦素信号是：1）在生长激素之后被删除 选择性消融 Lepr 外显子 1； 2) 在瘦素激增期间被瘦素拮抗剂阻断或 3) 被瘦素拮抗剂减弱 产妇营养不良。我们将在营养不良的动物中替换新生瘦素来检验这一假设 早期瘦素信号传导对于新生儿生长激素的成熟及其正常功能至关重要 成人。目标 2 研究将确定瘦素调节生长激素的机制。 这些研究将使用纯化的生长激素群体来确定瘦素的作用是否是由 减弱 MSI 介导的 Pou1f1、Tsh 和 Prl mRNA 抑制的信号通路。我们也会学习 miRNA 介导的 Gh 和 Ghrhr mRNA 抑制，并将采用公正的方法来识别 其他新的瘦素依赖性控制生长激素成熟的机制。这个贡献是 意义重大，因为它解决了瘦素在预防疾病方面的重要性这一全球性问题 产妇营养不良引起的代谢功能障碍，占全球疾病总数的 11% 负担，最终导致 35% 的儿童死亡。拟议的研究在概念上具有创新性，因为它 拓宽了我们对瘦素作用的理解，包括已知的垂体前叶细胞 重要的代谢传感器，并引入瘦素的新调控途径并利用方法学 生长激素纯化方面的进展。工作的预期成果是：（1）研究结果 将充分告知该领域瘦素在生长激素成熟和功能中的热带作用，以及（2）这项工作 将提供有关瘦素作用机制的信息，这些机制可能有针对性的治疗以预防 早期瘦素缺乏引起的严重代谢功能障碍。