Control of Reproduction by an Inhibitory RFamide Peptide

通过抑制性 RFamide 肽控制繁殖

• 批准号: 7615035
• 负责人: Lance J Kriegsfeld
• 金额: $ 22.16万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615035
• 关键词: Abbreviations; Address; Adverse effects; Affect; Birds; Brain; Butyric Acids; Cell Nucleus; Cells; Cholera Toxin; Circadian Rhythms; Communication; Diagonal Band of Broca; Diffuse; Dopamine; Dose; Electron Microscopy; Endocrine; Endocrine System Diseases; Endocrine system; Endocrinologist; Estradiol; Estrogen Receptors; Estrogen receptor positive; Estrogens; Estrous Cycle; Event; Feedback; Fiber; Follicle Stimulating Hormone; Gastrin releasing peptide; Genes; Glutamate Decarboxylase; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Health; Homeostasis; Hormonal; Hormones; Human; Hypothalamic structure; Injection of therapeutic agent; Jet Lag Syndrome; Label; Lateral; Lead; Luteinizing Hormone; Maintenance; Medial; Mesocricetus auratus; Mus; Names; Neural Pathways; Neuraxis; Neurons; Neurosecretory Systems; Pattern; Peptides; Peripheral; Physiologic pulse; Pituitary Gland; Play; Preoptic Areas; Prevention; Pro-Opiomelanocortin; Process; Production; Progesterone Receptors; Prolactin Release-Inhibiting Hormone; RFamide peptide; Radioimmunoassay; Rattus; Regulation; Reproduction; Reproductive system; Research Personnel; Risk; Rodent; Role; Schedule; Series; Signal Transduction; Steroids; Structure of nucleus infundibularis hypothalami; System; Text; Time; Transforming Growth Factors; Vasoactive Intestinal Peptide; Work; arginylphenylalaninamide; biotinylated dextran amine; circadian pacemaker; design; neuromechanism; neuronal cell body; novel; paraventricular nucleus; pituitary gonadal axis; programs; relating to nervous system; reproductive; reproductive axis; reproductive function; shift work; suprachiasmatic nucleus; tumor

DESCRIPTION (provided by applicant): The timing and coordination of the secretion of myriad hormones is necessary for the maintenance of homeostasis and optimal body functioning. Traditionally, endocrinologists have focused on the role of negative feedback mechanisms and neuroendocrine pulse generators as the primary mechanisms regulating the temporal pattern of hormone secretion. However, it is becoming increasingly clear that endogenous timing systems play a crucial role in this regulation. We recently found that cells containing a novel inhibitory peptide, gonadotropin-inhibitory hormone (GnlH), are highly localized in the brains of Syrian hamsters and other rodents, with fibers projecting diffusely from the septum to the caudal hypothalamus. Importantly, our pilot work shows that brain or peripheral injections of GnlH inhibit LH in a dose-dependent manner. Furthermore, the GnlH system projects to gonadotropin-releasing-hormone (GnRH) neurons, permitting direct, inhibitory control of GnRH secretion. Fibers originating in the brain clock located in the suprachiasmatic nucleus (SCN) form close appositions with GnlH cell bodies, providing a potential means of temporal control. Finally, GnlH cells contain estrogen receptors and respond to estradiol stimulation, suggesting that estrogen acts on these cells to regulate steroid negative feedback. Together, these findings indicate that the GnlH system is organized to modulate reproductive function and the hypothalamo-pituitary- gonadal (HPG) axis. The present proposal is designed to further explore the neuroanatomical and functional means by which the GnlH system is integrated with well understood mechanisms of reproductive control of the HPG axis. This proposal will establish the precise means of communication 1) from the endogenous circadian clock to the GnlH system, 2) from the GnlH system to the reproductive axis, and 3) the functional consequences of the interactions between this novel system and the reproductive axis. Disruptions in the timing of hormone secretion have pronounced adverse effects on human health. For example, jet lag and shift work lead to a variety of reproductive disturbances and an increased risk of developing endocrine-responsive tumors. This proposal seeks to understand the neural mechanisms responsible for hormonal timing to help guide the treatment/prevention of these endocrine disorders.

描述（由申请人提供）：各种激素分泌的时间和协调对于维持体内平衡和最佳身体功能是必要的。传统上，内分泌学家关注负反馈机制和神经内分泌脉冲发生器作为调节激素分泌时间模式的主要机制的作用。然而，越来越清楚的是，内源性定时系统在这种调节中起着至关重要的作用。我们最近发现，含有一种新型抑制肽--促性腺激素抑制激素（GnlH）的细胞高度定位于叙利亚仓鼠和其他啮齿动物的大脑中，纤维从隔膜弥漫性投射到下丘脑尾部。重要的是，我们的试点工作表明，脑或外周注射GnlH抑制LH的剂量依赖性的方式。此外，GnRH系统投射到促性腺激素释放激素（GnRH）神经元，允许直接抑制性控制GnRH分泌。起源于位于视交叉上核（SCN）中的脑时钟的纤维与GnlH细胞体形成紧密的并列，提供了一种潜在的时间控制手段。最后，GnlH细胞含有雌激素受体并对雌二醇刺激作出反应，表明雌激素作用于这些细胞以调节类固醇负反馈。总之，这些发现表明，GnLH系统的组织调节生殖功能和下丘脑-垂体-性腺（HPG）轴。本建议旨在进一步探索神经解剖学和功能的手段，GnLH系统集成的生殖控制的HPG轴的充分理解的机制。该提案将建立1）从内源性生物钟到GnlH系统，2）从GnlH系统到生殖轴，以及3）该新系统与生殖轴之间相互作用的功能后果的精确通信手段。激素分泌时间的中断对人类健康有明显的不利影响。例如，时差和轮班工作会导致各种生殖障碍，并增加患内分泌反应性肿瘤的风险。该提案旨在了解负责激素定时的神经机制，以帮助指导这些内分泌疾病的治疗/预防。