Upstream Regulation of Kiss1 Cells

Kiss1 细胞的上游调控

• 批准号: 7988587
• 负责人: Horacio O De La Iglesia
• 金额: $ 7.8万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7988587
• 关键词: Affect; Animal Model; Animals; Biological; Books; Brain; Cardiovascular system; Cell Nucleus; Cells; Chronic; Circadian Rhythms; Clinic Visits; Code; Contralateral; Data; Development; Disease; Dysmenorrhea; Efferent Pathways; Estradiol; Estrogens; Exhibits; Exposure to; FOS gene; Face; Fatigue; Female; Fertility; Fiber; Foundations; Frequencies; Gene Expression; Generations; Genes; Goals; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Health; Healthcare; Hour; Human; Hypothalamic structure; In Situ Hybridization; Intervention; Ipsilateral; KISS1R gene; Klinefelter' s Syndrome; Knowledge; Label; Laboratories; Lead; Lesion; Light; Luteinizing Hormone; Measures; Medical; Menstrual cycle; Mental Health; Messenger RNA; Modeling; Mus; Nature; Nervous System Physiology; Neurons; Neurosecretory Systems; New York; Nurses; Outcome; Output; Ovarian; Ovulation; Pacemakers; Pathway interactions; Pattern; Physiological; Pituitary Gland; Play; Pregnancy; Pregnancy Outcome; Preventive; Process; Psyche structure; Puberty; Rattus; Raven; Regulation; Regulatory Pathway; Reporting; Reproduction; Reproductive Health; Reproductive Physiology; Research; Rodent; Role; Schedule; Side; Signal Transduction; Site; Sleep; Sleep Stages; Source; Spontaneous abortion; Staging; System; Testing; Time; Tokyo; Vasopressins; Vertebrates; Woman; Work; Working Women; Workplace; base; circadian pacemaker; early onset; experience; female reproductive system; immunocytochemistry; kisspeptin; male; nerve supply; ovulation time; receptor; relating to nervous system; reproductive; reproductive axis; reproductive development; reproductive function; research study; sex; shift work; suprachiasmatic nucleus; therapy development

Ovulation depends on a surge in the release of luteinizing hormone (LH), which in turn depends on a surge of gonadotropin-releasing hormone (GnRH). In recent years, kisspeptin (KISS) has emerged as the most potent stimulator of GnRH and a key regulator of reproductive development and health in vertebrates, including humans. In females, KISS signaling to GnRH cells is critical for the induction of the LH surge. Despite the central role of KISS in reproduction and specifically in female reproductive development and fertility, little is known about the upstream regulators of neurons expressing Kiss1, the gene coding for KISS. Here we present preliminary results that indicate that Kiss1 expression and the expression of c-fos within Kiss1 neurons in female mice is under circadian regulation, and this regulation is dependent on the presence of high ovarian estrogen levels. The overall goal of this proposal is to determine the pathways by which the circadian system may regulate the activity of Kiss1 neurons. Our laboratory has developed a rat model of circadian desynchronization in which independent circadian outputs are associated with the desynchronized activity of anatomically identifiable subregions of the hypothalamic suprachiasmatic nucleus (SCN), the site of the mammalian master circadian pacemaker. Our preliminary data on this forced desynchronized rat model indicates that the gating of the luteinizing hormone (LH) surge is associated with the activity of the dorsomedial (dm) SCN irrespective of the activity of the ventrolateral (vl) SCN. Because the dmSCN is the main source of vasopressinergic efferent fibers, our hypothesis is that vasopressin (VP) release is a critical SCN signal to induce the LH surge and therefore to activate Kiss1 neurons in a circadian pattern. We propose experiments that test specific predictions of this hypothesis. We will test the prediction that SCN vasopressinergic fibers innervate Kiss1-expressing cells and that innervation of the Kiss1 neuronal network by SCN efferent fibers is critical to sustain the circadian regulation of Kiss1 and of c-fos expression within Kiss1 neurons, which are concomitant with the LH surge. We will use unilateral lesions of the SCN to ipsilaterally deplete the anteroventral periventricular nucleus of SCN efferent fibers. In these animals we will assess the level of asymmetric VP innervation of Kiss1 neurons as well as the asymmetry in the circadian regulation of Kiss1 expression and c-fos expression within Kiss1 cells. Our proposed studies will characterize the pathways and mechanisms by which the activity of the Kiss1 neuronal network is regulated. Specifically, we will determine how a critical component of the mechanisms leading to ovulation such as the circadian system regulates gene expression within Kiss1 cells. Because the activity of these neurons and the release of KISS are essential for normal ovulation, understanding the upstream regulators of Kiss1 neurons will be key to developing therapies to treat disorders of the hypothalamo-pituitary-ovarian axis.

排卵取决于黄体生成素（LH）的释放激增，而黄体生成素又取决于 促性腺激素释放激素（GnRH）激增。近年来，kisspeptin（KISS）已成为 GnRH最有效的刺激剂和脊椎动物生殖发育和健康的关键调节剂， 包括人类在女性中，KISS信号传递到GnRH细胞对于LH峰的诱导至关重要。 尽管KISS在生殖中，特别是在女性生殖发育中发挥着重要作用， 生育，很少有人知道上游调控神经元表达Kiss 1，基因编码的生育能力， 吻在这里，我们提出了初步结果，表明Kiss 1表达和c-fos表达 在雌性小鼠的Kiss 1神经元内， 卵巢雌激素水平高。本提案的总体目标是通过以下方式确定路径： 昼夜节律系统可能调节Kiss 1神经元的活动。我们的实验室培育出一种老鼠 昼夜节律去极化模型，其中独立的昼夜节律输出与 下丘脑视交叉上核解剖学上可识别的亚区的去兴奋活性 (SCN)哺乳动物主昼夜节律起搏器的位置。我们的初步数据显示 去卵巢大鼠模型表明，促黄体生成激素（LH）峰的门控与 背内侧（dm）SCN的活动与腹外侧（vl）SCN的活动无关。因为 dmSCN是加压素能传出纤维的主要来源，我们假设加压素（VP） 释放是一个关键的SCN信号，以诱导LH激增，因此激活Kiss 1神经元在昼夜节律 格局我们提出实验来检验这一假设的具体预测。 我们将测试SCN血管加压素能纤维支配Kiss 1表达细胞的预测， SCN传出纤维对Kiss 1神经元网络的神经支配对于维持昼夜节律至关重要。 调节Kiss 1和Kiss 1神经元内c-fos的表达，这与LH峰同时出现。 我们将使用单侧SCN损伤， SCN传出纤维。在这些动物中，我们将评估Kiss 1的不对称VP神经支配水平。 神经元以及Kiss 1表达和c-fos表达的昼夜节律调节的不对称性 Kiss 1细胞 我们提出的研究将表征的途径和机制，通过该活动的 Kiss 1神经元网络受到调节。具体来说，我们将确定如何一个关键组成部分， 导致排卵的机制，如昼夜节律系统调节Kiss 1细胞内的基因表达。 因为这些神经元的活动和KISS的释放对正常排卵至关重要， 了解Kiss 1神经元的上游调节因子将是开发治疗方法的关键。 下丘脑-垂体-卵巢轴紊乱。