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

• 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
• 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

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.

摘要 促性腺激素轴的激活需要下丘脑的脉冲式释放 十肽GnRH。在没有这些脉冲的情况下，繁殖受到阻碍。尽管 GnRH释放的这一关键特征，即控制GnRH释放的中枢机制的性质， 这种脉冲释放仍然是未知的。近年来，弓状核的Kiss 1神经元 原子核被认为是可能的候选者，以保持这个脉冲发生器通过 其共递质速激肽、神经激肽B（NKB）和强啡肽A的协同作用 (Dyn)这些神经元被称为KNDy神经元。我提出了一个模型， NKB刺激KNDy神经元释放kisspeptin，Dyn抑制KNDy神经元释放kisspeptin， 一种脉冲模式，然后转化为GnRH，因此LH，脉冲。 然而，我们最近的文件，其他速激肽（P物质，SP和 神经激肽A，NKA）可以激活KNDy神经元，增加一个额外的复杂层， 该模型重要的是，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。然而，我们最近观察到， 循环雌二醇（E2）水平，NKB和SP均引起LH释放的有效增加 以不依赖于kisspeptin的方式，这损害了先前的模型。 重要的是，KNDy神经元和GnRH神经元（尽管程度较低）表达KNDy。 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起作用以诱导LH释放。 本提案的总体目标是描述每种速激肽在免疫应答中的作用。 KNDy神经元与GnRH的小鼠LH脉冲的频率和幅度 神经元使用一系列互补的功能，神经解剖和遗传 问题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。