Role of Kiss1 neurons in the seasonal and circadian control of reproduction

Kiss1 神经元在生殖季节和昼夜节律控制中的作用

• 批准号: 7760162
• 负责人: ALEXANDER S KAUFFMAN
• 金额: $ 24.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760162
• 关键词: Adult; Animal Model; Axon; Binding; Brain; Brain region; Cell Nucleus; Cells; Circadian Rhythms; Coupled; Cues; Delayed Puberty; Development; Disease; Endocrine; Estrogens; Feedback; Female; Food; G Protein-Coupled Receptor 54; Genes; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Hamsters; Human; Hypothalamic structure; Infertility; Instruction; Ipsilateral; KISS1R gene; Kallmann Syndrome; Lead; Left; Link; Mammals; Mediating; Melatonin; Neurons; Neuropeptides; Neurosecretory Systems; Neurotransmitters; Pathway interactions; Pattern; Photoperiod; Physiological; Play; Prosencephalon; Proteins; Puberty; Regulation; Reproduction; Reproductive system; Research; Research Proposals; Role; Scientist; Sexual Maturation; Signal Transduction; Steroids; System; Time; circadian pacemaker; day length; design; frontier; insight; kisspeptin; nerve supply; neural circuit; neuromechanism; relating to nervous system; reproductive; reproductive axis; research study; suprachiasmatic nucleus

PROJECT SUMMARY (See instructions): The Kissi gene encodes proteins called kisspeptins, v^rhich bind to the G-protein coupled receptor GPR54. Kissl is expressed in discrete brain regions that regulate reproductioa and in mammals, induding humans, kisspeptins stimulate the secretion of gonadotropin-releasing hormone (GnRH) and gonadotropins (LH, FSH). Kissl neurons are themselves regulated by gonadal sex hormones, suggesting a crucial role for kisspeptin signaling in the negative and positive feedback regulation of reproduction. Although the stimulatory role of kisspeptin-GPR54 signaling in the control of GnRH secretion has been well-studied, the role of Kissl nemons in the environmental, circadian, and developmental regulation of reproductioivis much less cftaractenzea. ine goals or this research are to elucidate the physiological role Ofthe KiHlil system in the circadian, photoperiodic, and developmental control of GnRH secretion. The first objective is to evaluate the role of Kissl neurons in the drcadian-controlled pre-ovulatory LH surge. In females, the pre-ovulatory LH surge is coupled to a circadian oscillator in the suprachiasmatic nucleus (SCN). Althoiigh the rieural circuitry and neuroendocrine factors that mediate the SCN's control of the surge remain unidentified, evidence implicates the involvement of Kissl neurons. I will investigate whether Kissl neurons undergo circadian activation at the time of daily LH surges and determine whether there are direct neural cormections between the SCN and Kissl neurons (and if so, identify" the neurotransmitters involved in this circuitry). The second main objective is to evaluate the role of Kissl neurons in the seasonal control of reproduction and sexual maturation. It is known that seasoital reproduction and puberty onset are governed by pineal melatonin (MEL) secretion (which reflects day length), but the neural circuitry that integrates and relays MEL signals to GnRH neurons remains unidentified. I wiU assess the effects of photoperiod/MEL on the hypothalamic Kissl system, ascertain whether MEL's effects on Kissl neurons are direct or indirect, and determine how the regulation of Kissl neurons varies with developmental status (puberty). I will also comprehensively evaluate the roles of several candidate nuclei in relaying any indirect effects of MEL on Kissl neurons. Lastly, I will investigate how the irmervatipn of GnRH neurons by Kissl axons and the sensitivity oi Kissl neurons to feedback effects of sex steroids areregulated by photoperiod and developmental status.

项目总结（见说明）： Kissi基因编码称为kisspeptins的蛋白质，其与G蛋白偶联受体GPR 54结合。 Kissl在调节生殖的脑区和哺乳动物中表达，包括 在人类中，kisspeptins刺激促性腺激素释放激素（GnRH）的分泌， 促性腺激素（LH、FSH）。Kissl神经元本身受性腺性激素的调节，这表明 kisspeptin信号在生殖的负反馈和正反馈调节中起着关键作用。 尽管Kisspeptin-GPR 54信号在GnRH分泌控制中的刺激作用已经被证实， Kissl nemons在环境，昼夜节律和发育调节中的作用， reproductioivis much less cftaractenzea.本研究的主要目的是阐明 KiHlil系统在GnRH分泌的昼夜节律、光周期和发育控制中的作用的 第一个目的是评估Kissl神经元在药物控制的排卵前LH峰中的作用。 在女性，排卵前LH峰与视交叉上核的昼夜节律振荡器相耦合 （SCN）。尽管神经回路和神经内分泌因子介导了SCN的控制， 浪涌仍然不明，证据暗示参与Kissl神经元。我会调查 Kissl神经元是否在每日LH激增时经历昼夜节律激活， SCN和Kissl神经元之间存在直接的神经连接（如果是这样，请识别” 神经递质参与这一电路）。第二个主要目标是评估Kissl的作用 神经元在生殖和性成熟的季节性控制。据了解， 生殖和青春期的开始由松果体褪黑激素（MEL）分泌（反映白天）决定 长度），但整合和中继MEL信号到GnRH神经元的神经回路仍然存在 身份不明我将评估光周期/MEL对下丘脑Kissl系统的影响，确定MEL对Kissl神经元的影响是直接的还是间接的，并确定Kissl神经元的调节如何随发育状态（青春期）而变化。我还将全面评估几个候选核在中继MEL对Kissl神经元的任何间接影响中的作用。最后，我们将研究Kissl轴突对GnRH神经元的照射以及Kissl神经元对性激素反馈效应的敏感性如何受光周期和发育状态的调节。