Dissecting the Role of Tachykinins in the Generation of GnRH Pulses

剖析速激肽在 GnRH 脉冲生成中的作用

基本信息

批准号：
9921213
负责人：
Victor Manuel Navarro
金额：
$ 34.77万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-28 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9921213
关键词：
Achievement Affect Agonist Amenorrhea Brain Cells Complex Delayed Puberty Dependovirus Disease Dynorphins Enterobacteria phage P1 Cre recombinase Estradiol Etiology Exhibits Fertility Financial compensation Frequencies Generations Genes Genetic Genetic study Goals Gonadal Steroid Hormones Gonadal structure Gonadotropin Hormone Releasing Hormone Hormonal Hormone secretion Hypothalamic structure Infertility KISS1 gene Knock-out Maintenance Messenger RNA Methods Modeling Molecular Monkeys Mus Nature Neurokinin A Neurokinin B Neurons Ovarian Pathway interactions Patients Pattern Pharmacology Study Phenotype Physiologic pulse Pituitary Gland Proteins Puberty Reproduction Rodent Role Series Signal Transduction Structure of nucleus infundibularis hypothalami Substance P TAC1 gene TACR1 gene TACR3 gene Tachykinin Tachykinin Receptor Testing Thinking Translating experimental study knock-down mouse model receptor reproductive reproductive function small hairpin RNA

项目摘要

ABSTRACT The activation of the gonadotropic axis requires the pulsatile release of the hypothalamic decapeptide GnRH. Reproduction is thwarted in the absence of these pulses. Despite this critical feature of GnRH release, the nature of the central mechanisms that govern this pulsatile release remain unknown. In recent years, Kiss1 neurons of the arcuate nucleus have been posed as likely candidates to hold this pulse generator through the coordinated action of its co-transmitters tachykinin neurokinin B (NKB) and dyrorphin A (Dyn), which has led these neurons to be termed KNDy neurons. I propose a model in which NKB stimulates and Dyn inhibits kisspeptin release from KNDy neurons leading to a pulsatile pattern that would then be translated into GnRH, and therefore LH, pulses. However, we have recently documented that other tachykinins (substance P, SP and neurokinin A, NKA) can activate KNDy neurons, adding an additional complex layer to this model. Importantly, recent studies in rodents and monkeys indicate that the action of tachykinins to induce LH release happens at the level of KNDy neurons and is therefore kisspeptin-dependent. However, we have recently observed that in the presence of circulating estradiol (E2) levels, both NKB and SP evoke a potent increase in LH release in a kisspeptin-independent manner, which compromises the previous model. Importantly, KNDy neurons and GnRH neurons (albeit to a lesser extend) express the receptors for SP (Tacr1) and NKB (Tacr3), suggesting that tachykinins may be able to act at both neuronal levels to induce LH release under the right sex steroid conditions. The overall goal of this proposal is to characterize the role of each tachykinin in the frequency and amplitude of LH pulses in the mouse at the KNDy neuron vs GnRH neuron using a series of complementary functional, neuroanatomical and genetic studies. The successful completion of this proposal will offer new strategies to treat reproductive disorders affecting GnRH secretion.

抽象的促性腺轴的激活需要下丘脑的脉冲式释放十肽 GnRH。如果没有这些脉冲，繁殖就会受到阻碍。尽管 GnRH 释放的这一关键特征，即控制的中央机制的性质这种脉冲释放仍然未知。近年来，弓形神经元Kiss1 原子核已被认为是通过其共递质速激肽神经激肽 B (NKB) 和肌啡肽 A 的协调作用 (Dyn)，这使得这些神经元被称为 KNDy 神经元。我提出了一个模型 NKB 刺激而 Dyn 抑制 KNDy 神经元释放 Kisspeptin，从而导致一种脉动模式，然后将被转化为 GnRH 脉冲，从而转化为 LH 脉冲。然而，我们最近记录了其他速激肽（物质 P、SP 和神经激肽 A，NKA）可以激活 KNDy 神经元，添加一个额外的复杂层这个模型。重要的是，最近对啮齿动物和猴子的研究表明，速激肽诱导 LH 释放发生在 KNDy 神经元水平，因此 Kisspeptin 依赖性。然而，我们最近观察到，在存在循环雌二醇 (E2) 水平，NKB 和 SP 都会引起 LH 释放的有效增加以独立于 Kisspeptin 的方式，这损害了之前的模型。重要的是，KNDy 神经元和 GnRH 神经元（尽管程度较小）表达 SP (Tacr1) 和 NKB (Tacr3) 受体，表明速激肽可能能够在适当的性类固醇条件下，在两个神经元水平上发挥作用，诱导 LH 释放。该提案的总体目标是描述每种速激肽在小鼠 KNDy 神经元与 GnRH 处 LH 脉冲的频率和幅度神经元使用一系列互补的功能、神经解剖学和遗传研究。该提案的成功完成将为治疗提供新的策略影响 GnRH 分泌的生殖障碍。