Interactions of dynorphin, NKB, and kisspeptin in control of GnRH secretion

强啡肽、NKB 和 Kisspeptin 在控制 GnRH 分泌中的相互作用

基本信息

批准号：
8840758
负责人：
ROBERT L. GOODMAN
金额：
$ 3.33万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8840758
关键词：
Address Agonist Amenorrhea Anatomy Animals Anorexia Nervosa Applications Grants Area Attention Automobile Driving Blood Cells Characteristics Contraceptive Agents Defect Development Disease Dynorphins Estradiol Estrous Cycle Feedback Female Foundations Future Gene Mutation Genes Genetic Goals Gonadal Steroid Hormones Health Human Individual Infertility Klinefelter&apos s Syndrome Knowledge Lead Mediating Menstrual cycle Modeling Molecular Monitor Mus Mutation Names Neurokinin B Neuromedin K Receptor Neuronal Plasticity Neurons Neuropeptides Neurosecretory Systems Opioid Peptide Ovarian Ovarian Cycles Pathology Pathway interactions Peptides Phenotype Physiologic pulse Physiological Play Population Primates Progesterone Reporting Reproduction Research Rodent Rodent Model Role Shapes Sheep Signal Transduction Steroids Structure of nucleus infundibularis hypothalami Synapses Synaptic plasticity Syndrome Tachykinin Techniques Testing Work awake base design endogenous opioids insight interest kisspeptin knockout gene median eminence neuronal cell body novel receptor relating to nervous system reproductive reproductive function reproductive neuroendocrinology research study

项目摘要

DESCRIPTION (provided by applicant): GnRH secretion is critical for normal human reproduction and defects in GnRH/LH pulses and the preovulatory GnRH/LH surge contribute to many common reproductive pathologies, including amenorrhea, polycystic ovarian syndrome (PCOS), and infertility associated with anorexia nervosa. Despite the long-standing recognition of the importance and functions of the GnRH neuroendocrine system, a detailed knowledge of the pathways by which endogenous gonadal steroid hormones are conveyed to GnRH neurons and control their secretory activity during the ovarian cycle remains elusive. Understanding of the neural substrates responsible for GnRH secretion has been revolutionized in the last few years by identification of the key role of a neuronal subpopulation in the arcuate nucleus that co-expresses kisspeptin, neurokinin B (NKB) and dynorphin (termed "KNDy" neurons). Genetic mutations in two of the three KNDy peptides, kisspeptin and NKB, lead to human infertility, and there is strong evidence that the third peptide conveys the inhibitory influence of progesterone on GnRH neurons. A number of features of the KNDy neurons suggest that they may play a key role in episodic GnRH secretion, but this hypothesis and the precise role of each of the KNDy peptides remains to be tested. In the current proposal, we will use a combination of physiological, pharmacological, molecular and neuroanatomical approaches to address this and other questions. First, we will determine if the KNDy cell network is critical for episodic GnRH secretion, examining the effects of disrupting each of the KNDy peptides on GnRH pulse shape. Second, we will address the gap in knowledge concerning the normal physiological role of NKB by determining its role in steroid feedback control of GnRH/LH pulses and the GnRH/LH surge. Finally, we will address key unresolved questions about the anatomy of KNDy cells, including the presence of direct synaptic connections between KNDy and GnRH neurons, and the possibility of synaptic plasticity in these connections during the normal estrous cycle. These questions will be addressed using the female sheep, a model that possesses several unique advantages including the ability to directly monitor GnRH in hypophysial portal blood in awake, unanesthesized animals, and an estrous cycle whose neuroendocrine control closely resembles that of the human menstrual cycle. The proposed studies will provide new information on the mechanisms underlying GnRH secretion and the role of NKB that may lay the foundation for the development of better treatments for pathological disruptions of reproductive function, and the design of novel contraceptive techniques

描述（由申请人提供）：GNRH分泌对于正常的人类繁殖和GNRH/LH脉冲中的缺陷至关重要，而排卵前的GNRH/LH激增有助于许多常见的生殖病理，包括闭经，多囊性卵巢综合征（PCOS）和地下综合症（PCOS），以及神经性厌食症。尽管长期以来对GNRH神经内分泌系统的重要性和功能有了长期的认识，但对内源性性腺类固醇激素的详细知识传达给了GnRH神经元并控制其在卵巢周期中的分泌活性仍然难以捉摸。在过去的几年中，了解对GNRH分泌负责的神经底物的理解已通过鉴定神经元亚群在弧形核中的关键作用进行了革命，该核核共表达了亲吻蛋白，神经蛋白B（NKB）和二极释（称为“ Kndy”神经元，“ kndy”神经元” ）。三种KNDY肽中的两个Kisspeptin和NKB中的两个遗传突变导致人类不育症，并且有强有力的证据表明，第三肽传达了孕酮对GNRH神经元的抑制作用。 KNDY神经元的许多特征表明它们可能在情节性GNRH分泌中起关键作用，但是该假设和每种KNDY肽的精确作用仍有待测试。在当前的建议中，我们将使用生理，药理，分子和神经解剖学方法的结合来解决这个问题和其他问题。首先，我们将确定KNDY细胞网络对于偶发性GNRH分泌至关重要，检查破坏每个Kndy肽对GnRH脉冲形状的影响。其次，我们将通过确定其在GNRH/LH脉冲的类固醇反馈控制中的作用和GnRH/LH激增来解决有关NKB正常生理作用的知识差距。最后，我们将解决有关KNDY细胞解剖结构的关键问题，包括KNDY和GNRH神经元之间的直接突触连接，以及在正常发情循环中这些连接中突触可塑性的可能性。这些问题将使用雌性绵羊解决，该模型具有多个独特的优势，包括能够直接监测醒目的垂直血液中的GNRH，单人觉动物，以及一个发情循环，其神经内分泌控制与人类月经周期的神经内分泌控制非常相似。拟议的研究将提供有关GNRH分泌基础机制的新信息以及NKB的作用，这可能奠定了更好地治疗生殖功能的更好处理的基础，以及新型避孕技术的设计