Role of the Melanocortin-3 Receptor in Regulation of the HPG Axis

Melanocortin-3 受体在 HPG 轴调节中的作用

基本信息

批准号：
10517280
负责人：
Danielle Tiffany Porter
金额：
$ 6.75万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10517280
关键词：
ART protein Acute Agonist Anatomy Biological Models Calcium Cell Nucleus Communication Data Defect Diagnosis Disease Drug Targeting Event Exhibits Fasting Feeding behaviors Female Fertility Frequencies Functional disorder Future Gestational Diabetes Goals Homeostasis Hypothalamic structure Image Infertility Injections KISS1 gene Knockout Mice Lead Length Link Luteinizing Hormone Measures Mediating Melanocortin 3 Receptor Melanocortin 4 Receptor Messenger RNA Metabolic Metabolism Modeling Mus Neural Pathways Neuroendocrinology Neurons Pathologic Pathway interactions Peripheral Pharmacology Physiologic pulse Physiological Physiology Pituitary Gland Play Polycystic Ovary Syndrome Positioning Attribute Postmenopause Pregnancy Prevention strategy Process Regulation Reproduction Reproductive Physiology Research Resources Role Sheep Site Structure of nucleus infundibularis hypothalami System Testing Therapeutic Therapeutic Intervention Training Transgenic Organisms Virus Weight Gain alpha-Melanocyte stimulating hormone antagonist career disease phenotype energy balance gamma-Aminobutyric Acid gonad function hormonal signals hypothalamic pituitary gonadal axis in vivo insight knock-down microendoscopy mouse model neural circuit neurophysiology neurotransmission novel paraventricular nucleus receptor relating to nervous system reproductive reproductive axis reproductive function reproductive success reproductive system disorder response small hairpin RNA tool

项目摘要

To assure adequate energy resources for the energetically demanding process of reproduction, central reproductive physiology is influenced by hormonal and neural signals of energy balance. As a result, maladaptive changes in energy homeostasis in either the positive or negative direction can exert dramatic effects on reproductive success and fertility. Despite the importance of physiological interactions between metabolic state and reproduction, the underlying mechanisms and neural pathways linking metabolism and reproduction are not fully understood. The central melanocortin system has been demonstrated to be involved in the integration of reproduction and metabolism. Previous studies have determined that alpha melanocyte stimulating hormone (α-MSH), agouti related protein (AgRP), and melanocortin 4 receptor (MC4R) modulate multiple aspects of reproductive function. In this proposal, we provide data demonstrating that the melanocortin-3 receptor (MC3R) plays critical, bidirectional roles in integration of energy and reproductive states. We further show defects in the hypothalamic-pituitary-gonadal axis in MC3R KO mice. Therefore, the long-term goal of this project is to further understand the role of MC3R in mediating reproductive function in both healthy and disease phenotypes. In the first aim, I will examine reproductive physiology and utilize transgenic tools and pharmacology to test that the MC3R modulates LH pulsatility by regulating GABAergic release in AgRP terminal sites. The second aim will examine a potential mechanism by which MC3R might regulate LH pulsatility. This aim will use endomicroscopic imaging to test the hypothesis that the MC3R can reduce LH pulsatility by increasing GABAergic release in AgRP terminal sites on arcuate kisspeptin neurons. Together, these studies will provide further insight into the role of the melanocortin system, in particular MC3R, in regulating the HPG axis and may reveal new targets for future therapeutic intervention for treatment of reproductive disorders, including PCOS.

为了实现足够的能量资源来进行能量苛刻的繁殖过程，中央生殖生理受到荷尔蒙和神经平衡信号的影响。结果，在正方向或负方向上能量稳态的不良适应性变化会对生殖成功和生育能力产生巨大影响。尽管代谢状态与繁殖之间的物理相互作用很重要，但尚未完全了解与代谢和繁殖联系的基本机制和神经途径。已证明中央黑色皮质素系统与繁殖和代谢的整合有关。先前的研究已经确定α黑素细胞刺激马酮（α-MSH），Agouti相关蛋白（AGRP）和黑色素皮质素4受体（MC4R）调节生殖功能的多个方面。在此提案中，我们提供了数据，证明黑色素皮质素3受体（MC3R）在能量和生殖状态的整合中起着至关重要的双向作用。我们进一步显示了MC3R KO小鼠的下丘脑 - 垂体 - 基达轴的缺陷。因此，该项目的长期目标是进一步了解MC3R在健康和疾病表型中介导生殖功能中的作用。在第一个目标中，我将检查生殖生理学，并利用转基因工具和药理学来测试MC3R通过调节AGRP终端位点中的GABAergic释放来调节LH脉动性。第二个目标将检查MC3R可能调节LH脉动性的潜在机制。该目标将使用伸长搏动性来检验以下假设：MC3R可以通过在ARCRP Kisspeptin神经元上增加AGRP末端位点的GABA能释放来降低LH脉动性。总之，这些研究将进一步洞悉黑素皮质素系统，尤其是MC3R在控制HPG轴上的作用，并可能揭示新的靶标，用于治疗包括PCOS在内的生殖障碍的未来治疗干预措施。