Nutritional Regulation of Luteinizing Hormone Secretion

黄体生成素分泌的营养调节

• 批准号: 10501026
• 负责人: Casey C Nestor
• 金额: $ 45.2万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501026
• 关键词: Address; Animal Model; Animals; Biological Assay; Cardiovascular Diseases; Cell Culture Techniques; Cells; Chronic; Cues; Delayed Puberty; Detection; Development; Drug Delivery Systems; Eating; Eating Disorders; Energy Intake; Female; Fertility; Fluorescent in Situ Hybridization; Future; GNRH1 gene; Glucose; Goals; Gonadotropin Hormone Releasing Hormone; Health; Hormone secretion; Human; Hypothalamic structure; Immune; Immune signaling; Immune system; Immunohistochemistry; In Vitro; Individual; Infusion procedures; Insulin; Interleukin-1 beta; KISS1 gene; Lead; Link; Luteinizing Hormone; Malnutrition; Mediating; Melanocortin 3 Receptor; Mental Depression; Metabolic; Microglia; Modeling; Neurons; Nutritional; Obesity; Outcome; Peptide Signal Sequences; Peptides; Phenotype; Physiology; Play; Puberty; Regulation; Reproduction; Research; Role; Sexual Maturation; Sheep; Signal Transduction; Structure of nucleus infundibularis hypothalami; Substance abuse problem; Synapses; Techniques; Therapeutic; Therapeutic Intervention; Time; Work; anakinra; design; disorder prevention; disorder risk; experimental study; feeding; improved; in vivo; innovation; insight; male; melanocortin receptor; nerve supply; novel; nutrition; prevent; pubertal timing; reproductive success

Project Summary The long-term goal of the proposed research is to determine the central mechanisms by which undernutrition and realimentation impact reproduction through regulation of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion, using male and female sheep as an animal model. Puberty onset integrates various internal and external cues resulting in an increased release of GnRH from the hypothalamus that imparts the capacity for sexual maturation and reproductive success. Inadequate energy intake (undernutrition) has a significant negative impact on GnRH, and subsequently LH secretion, thereby delaying puberty onset. However, the central mechanisms responsible for the suppression of GnRH/LH secretion during undernutrition or the increase of GnRH/LH secretion following re-feeding (realimentation) remain largely unknown. Thus, the objectives of this proposal are 1) to determine the role that AgRP signaling plays in regulating GnRH and kisspeptin neurons during undernutrition and realimentation, and 2) to determine the role that microglia play in regulating GnRH and kisspeptin neurons during undernutrition and realimentation. In Aim 1, we will characterize changes in AgRP signaling in GnRH and kisspeptin neurons in feed-restricted (FR) sheep, examine the in vivo effect of AgRP immunoneutralization in the arcuate nucleus (ARC) of the hypothalamus on LH secretion in FR sheep, and characterize changes in AgRP signaling in GnRH and kisspeptin neurons in refed sheep. In Aim 2, we will characterize changes central immune signaling in GnRH and kisspeptin neurons in FR sheep, examine the in vivo effect of central infusion of an interleukin-1 receptor antagonist on LH secretion in FR sheep, characterize changes in central immune signaling in GnRH and kisspeptin neurons in refed sheep, and examine the in vitro effect of low glucose and insulin on microglia phenotype and function. Herein, with our expertise in whole-animal physiology, in vivo drug delivery, immunohistochemistry, and in vitro cell culture we have designed experiments to apply the highly innovative technique of a fluorescent in situ hybridization assay, RNAscope, for detection of signaling components for AgRP (Aim 1) and interleukin-1β (Aim 2). The proposed experiments will not only address the neuronal networks by which changes in metabolic state impact reproduction, but also provide important insight into the role the immune system likely plays. Thus, this work will provide a greater understanding of how undernutrition impacts central networks that regulate GnRH/LH secretion and yield novel and critical insight that may allow for better control of the timing of puberty, and ultimately lead to improved human health through prevention of disorders (e.g. cardiovascular disease and depression) associated with delayed puberty.

项目摘要 拟议研究的长期目标是确定中心机制 营养和实现通过调节促性腺激素释放来影响繁殖 Horseone（GnRH）和黄体式马龙（LH）分泌，使用雄性和雌性绵羊作为动物 模型。青春期发作整合了各种内部和外部提示，从而增加了 从下丘脑的gnrh，不可能实现性成熟和复制成功的能力。 能量摄入不足（营养不良）对GNRH产生重大负面影响，随后 LH分泌，从而延迟青春期发作。但是，负责 抑制营养不良期间的GnRH/LH分泌或GNRH/LH分泌的增加 重新喂养（实现）仍然未知。那就是该提议的目标是1） 确定AGRP信号在调节GNRH和Kisspeptin神经元中的作用 营养不良和实现，以及2）确定小胶质细胞在调节GNRH和 营养不良和实现过程中的亲肽神经元。在AIM 1中，我们将描述更改 GNRH中的AGRP信号传导和饲料限制（FR）绵羊中的Kisspeptin神经元，检查体内效应 下丘脑的弧形核（ARC）在FR中分泌下的AgRP免疫中和 绵羊，描述了GNRH中AGRP信号的变化，而绵羊中的亲吻蛋白神经元。 AIM 2，我们将表征GNRH中的中央免疫信号传导的变化，而FR中的Kisspeptin神经元 绵羊，检查中央输注白介素-1受体拮抗剂对LH分泌的体内效应 在Fr绵羊中，表征GNRH中央免疫信号传导的变化和refed的Kisspeptin神经元的变化 绵羊，检查低葡萄糖和胰岛素对小胶质细胞表型和功能的体外作用。 在此，我们在整个动物生理学方面的专业知识，体内药物输送，免疫组织化学以及 体外细胞培养我们设计了实验以应用荧光的高度创新技术 原位杂交分析，rnascope，用于检测AGRP的信号成分（AIM 1）和 白介素1β（AIM 2）。提出的实验不仅将解决神经元网络 代谢状态影响繁殖的变化，但也提供了对免疫作用的重要见解 系统可能会播放。这项工作将对营养不足的影响有更深入的了解 调节GNRH/LH分泌并产生新颖和关键见解的中央网络，可能允许 更好地控制青春期的时机，并最终通过预防来改善人类健康 与青春期延迟有关的疾病（例如心血管疾病和抑郁症）。