LHRH PULSE GENERATION AND STEROID FEEDBACK

LHRH 脉冲产生和类固醇反馈

• 批准号: 8358195
• 负责人: Ei Terasawa-Grilley
• 金额: $ 15.64万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358195
• 关键词: Animals; Biological Assay; Calcium Oscillations; Characteristics; Contraceptive Agents; Development; Endocrinology; Epigenetic Process; Estradiol; Estrogen Receptor alpha; Feedback; Funding; G-Protein-Coupled Receptors; Gene Expression; Generations; Genes; Grant; Hypothalamic structure; In Vitro; Infertility; Mediating; Monkeys; Mus; National Center for Research Resources; Neurons; Peptides; Periodicity; Physiologic pulse; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Services; Source; Steroids; United States National Institutes of Health; Wisconsin; age related; cost; demethylation; neuronal cell body; nonhuman primate; receptor; reproductive function; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To understand the mechanism of LHRH pulse generation and the mechanism of steroid action on LHRH neurons. DESCRIPTION: Pulsatile release of LHRH from the hypothalamus is essential for normal reproductive function, yet the mechanism of GnRH pulse generation is unclear. We cultured GnRH neurons originating from the olfactory pit/placode region and characterized the cellular mechanism of GnRH pulse generation. The periodicity of peptide release and bursting activity of GnRH neurons were much slower than mouse GnRH neurons, although many characteristics in monkey GnRH neurons are similar to those described for mice. The aim of this study is to understand the mechanism of GnRH pulse generation and the mechanism of steroid action on GnRH neurons. PROGRESS: We have made three important discoveries. First, primate GnRH neuronal maturation is characterized by age-dependent development of spontaneous synchronizing [Ca2+]i oscillations, pulsatile peptide release, increased GnRH gene expression and demethylation of a 5' CpG rich region of the GnRH gene. Second, rapid action of estradiol inducing intracellular calcium oscillations and GnRH release is mediated by neither estrogen receptor alpha nor beta. Rather, it appears to be, in part, mediated by the 7-transmembrane G-protein coupled receptor, GPR30 as well as a STX- sensitive receptor. Third, GnRH neurons releases the decapeptide from the cell body and neuroprocesses. These exciting findings are extremely important for the development of contraceptive tools and treatment of infertility. This research used WNPRC Animal Services and Assay Services. PUBLICATIONS: Terasawa, E., Kurian, J.R., Guerriero, K.A., Kenealy, B.P., Hutz, E.D., and Keen, K.L. Recent discoveries on the control of GnRH neurons in nonhuman primates. J. Neuroendocrinol. 22:630-638, 2010. PMID: 20456608, PMCID: PMC2908205. Kurian J.R., Keen, K.L., and Terasawa, E. 2010 Epigenetic changes coincide with in vitro primate GnRH neuronal maturation. Endocrinology 151:5359-5368. PMID: 20861233, PMCID: PMC2954729.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 目的：了解LHRH脉冲的产生机制， 类固醇对LHRH神经元作用的机制。 产品说明： 下丘脑脉冲性释放LHRH对正常生殖功能至关重要 功能，但GnRH脉冲产生的机制尚不清楚。我们培养了GnRH 起源于嗅窝/基板区的神经元， GnRH脉冲产生的细胞机制。肽释放的周期性和 GnRH神经元的爆发活动比小鼠GnRH神经元慢得多， 尽管猴GnRH神经元的许多特征与 描述老鼠。本研究的目的是了解GnRH的作用机制 脉冲的产生和类固醇对GnRH神经元的作用机制。 进展： 我们有三个重大发现。第一，灵长类GnRH神经元成熟 其特征是自发同步的年龄依赖性发展 [Ca2+]i振荡，脉冲肽释放，增加GnRH基因表达， GnRH基因的5' CpG富集区的去甲基化。第二，快速行动 雌二醇诱导细胞内钙振荡和GnRH释放是由 既不是雌激素受体α也不是β。相反，它似乎在一定程度上， 通过7-跨膜G蛋白偶联受体GPR 30以及STX- 敏感受体第三，GnRH神经元从细胞体释放十肽 和神经过程。这些令人兴奋的发现对于 开发避孕工具和治疗不孕症。 本研究使用WNPRC Animal Services和Assay Services。 出版物： Terasawa，E.，Kurian，J.R.，Guerriero，K.A.，Kenealy，B.P.，Hutz，E. D.，和Keen，K.L. 非人灵长类中GnRH神经元控制的最新发现。J. 神经内分泌素22：630-638，2010. PMID：20456608，PMCID：PMC2908205。 Kurian J.R. Keen，K.L.，和Terasawa，E. 2010年，表观遗传学的变化与 体外灵长类GnRH神经元成熟。内分泌学151：5359-5368。PMID： 20861233，PMCID：PMC2954729。