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激素（LH）的释放，这又取决于 促性腺激素释放激素（GNRH）的激增。近年来，Kisspeptin（KISS）已成为 GNRH的最有效刺激剂，以及脊椎动物生殖发展和健康的关键调节剂， 包括人类。在女性中，对GNRH细胞的亲吻信号对于LH激增的诱导至关重要。 尽管亲吻在繁殖中，特别是在女性生殖发育中的核心作用， 生育力，对表达KISS1的神经元的上游调节剂知之甚少，该基因编码为 吻。在这里，我们提出初步结果，表明Kiss1表达和C-Fos的表达 在雌性小鼠中的Kiss1神经元中，受昼夜节律的调节，该调节取决于 卵巢高雌激素水平的存在。该提案的总体目标是确定路径 昼夜节律系统可以调节KISS1神经元的活动。我们的实验室已经发展了老鼠 昼夜节律模型，其中独立的昼夜节目与 下丘脑上脑核的解剖学上可识别的子区域的干燥活性 （SCN），哺乳动物大师昼夜节奏起搏器的所在地。我们对此强迫的初步数据 异步大鼠模型表明，黄体生成激素（LH）的门控与 背侧（DM）SCN的活性与腹外侧（VL）SCN活性无关。因为 DMSCN是加压素能传出纤维的主要来源，我们的假设是加压素（VP） 释放是诱导LH激增的关键SCN信号，因此激活昼夜节律中的Kiss1神经元 图案。我们提出了测试该假设的特定预测的实验。 我们将测试SCN加压素能纤维神经表达KISS1的细胞和 SCN传出纤维对KISS1神经元网络的神经支配对于维持昼夜节律至关重要 KISS1和K-FOS表达的调节，与LH激增伴随着Kiss1神经元中的C-Fos表达。 我们将使用SCN的单侧病变来耗尽前腹脑室核的核 SCN发出的纤维。在这些动物中，我们将评估Kiss1的不对称VP神经支配的水平 神经元以及昼夜节律调节中的不对称性和C-FOS表达 在Kiss1细胞中。 我们提出的研究将表征其活性的途径和机制 KISS1神经元网络受到调节。具体来说，我们将确定如何的关键组成部分 导致排卵的机制，例如昼夜节律系统，调节基斯1细胞中的基因表达。 因为这些神经元的活性和亲吻的释放对于正常排卵至关重要，所以 了解KISS1神经元的上游调节剂将是开发治疗疗法的关键 下丘脑 - 垂体 - 卵巢轴的疾病。