The role of neurokinin B in the generation of menopausal flushes

神经激肽 B 在更年期潮红产生中的作用

• 批准号: 7505149
• 负责人: NAOMI E RANCE
• 金额: $ 27.76万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7505149
• 关键词: Ablation; Affect; Agonist; Anatomy; Animal Model; Area; Behavior; Behavioral; Biology; Brain; Brain Stem; Central Nervous System Diseases; Cutaneous; Data; Disease; Estrogen Receptors; Estrogen Replacements; Estrogens; Etiology; Exhibits; Exposure to; Face; Failure; Feedback; Flushing; Gene Expression; Generations; Gonadal Steroid Hormones; Gonadotropins; Heating; Hot flushes; Human; Hypertrophy; Hypothalamic structure; Indium; Individual; Laboratories; Laboratory Study; Maintenance; Maps; Menopause; Messenger RNA; Microinjections; Morphology; Motor Activity; Neurokinin B; Neuromedin K Receptor; Neurons; Neuropeptide Gene; Neurosecretory Systems; Numbers; Ovarian; Peptides; Physiologic Thermoregulation; Physiological; Play; Postmenopause; Public Health; Quality of life; Rattus; Receptor Activation; Regulation; Reproduction; Role; Secondary to; Skin Temperature; Structure of nucleus infundibularis hypothalami; Sweat; Sweating; Symptoms; System; TAC1 gene; Tachykinin Receptor; Tail; Temperature; Testing; Vasodilation; Vasodilation disorder; Withdrawal; Woman; design; insight; midbrain central gray substance; neural circuit; novel; preoptic nucleus; receptor; reproductive; reproductive axis; research study; tool

DESCRIPTION (provided by applicant): One of the most prominent symptoms of menopause is the hot flush, a disorder of central hypothalamic thermoregulation. Despite the unprecedented numbers of individuals affected, there is little understanding of the etiology of flushes and few laboratories are studying the basic biology of this phenomenon. Hot flushes are caused by estrogen withdrawal and consist of the coordinated activation of the physiologic mechanisms to dissipate heat (cutaneous vasodilatation, sweating and behavioral changes). Integration of the hypothalamic control centers for thermoregulation and reproduction is likely to be a key element in the mechanism of flushes. In our previous studies, we described dramatic changes in the morphology and gene expression of estrogen receptor-containing NKB mRNA containing neurons in the infundibular (arcuate) nucleus of postmenopausal women. Extensive evidence gathered in animal models has shown that the increase in NKB gene expression in postmenopausal women is secondary to loss of ovarian estrogen. We hypothesize that these NKB neurons play a role in the activation of thermoregulatory vasodilatation and therefore could be involved in the generation of menopausal flushes. We have now collected substantial pilot data in support of this hypothesis and have evidence of a novel neural circuit whereby estrogen-withdrawal activates heat dissipation effectors. We postulate that estrogen-responsive NKB neurons in the rat arcuate nucleus activate thermoregulatory vasodilatation via projections to NK3 receptor- expressing neurons in the median preoptic nucleus (MnPO), an important regulatory center for autonomic function. The present proposal will focus on this hypothesis. In specific aim 1, we will use morphologic tools to examine relationship between estrogen-responsive NKB neurons in the rat arcuate nucleus and the CNS centers controlling thermoregulatory vasodilatation. Specific aim 2 will test the hypothesis that NK3 receptor activation of MnPO neurons stimulates heat dissipation effectors in the rat. Specific aim 3 will evaluate whether interference with the function of NK3 receptor-expressing MnPO neurons reduces tail skin temperature or alters the thermoregulatory axis in ovariectomized rats. Specific aim 4 will determine if NK3 receptor mRNA is expressed in neurons in the human MnPO. These studies will provide novel insights into the potential relationship between the changes in hypothalamic gene expression in postmenopausal women and the inappropriate activation of heat dissipation mechanisms that characterize the hot flush. Understanding the mechanisms of hot flushes is critical for the ultimate design of appropriate therapies. A major feature of menopause is the hot flush, which is considered to be a disorder of central nervous system thermoregulation. Hot flushes are caused by loss of estrogen and are characterized by inappropriate activation of the physiological systems that remove heat from the body (heat dissipation). Currently, no safe and efficacious treatment is available, despite the fact that hot flushes may severely impact the quality of life in many individuals. In our previous research studies, we discovered that a group of neurons expressing the peptide neurokinin B (NKB) exhibit increased gene expression in the hypothalamus of postmenopausal women. We hypothesize that these NKB neurons play a role in the physiologic mechanisms to dissipate heat and therefore could be involved in the generation of hot flushes. The present proposal is designed to test this hypothesis. PUBLIC HEALTH RELEVANCE: These studies would be the first to relate the changes in hypothalamic gene expression in postmenopausal women to one of the most prominent symptoms of menopause. Little is understood about the mechanisms of hot flushes and there are only a few laboratories that study the basic biology of this problem. Understanding the mechanisms of hot flushes would greatly facilitate the design of appropriate treatments for these symptoms.

描述（由申请人提供）：更年期最突出的症状之一是潮热，这是一种中枢下丘脑体温调节障碍。尽管受影响的人数空前，但人们对潮红的病因知之甚少，也很少有实验室正在研究这种现象的基本生物学。潮热是由雌激素撤退引起的，由散热生理机制的协调激活（皮肤血管舒张、出汗和行为改变）组成。下丘脑温度调节和生殖控制中心的整合可能是潮红机制的关键因素。在我们之前的研究中，我们描述了绝经后女性漏斗（弓形）核中含有雌激素受体的NKB mRNA神经元的形态和基因表达的巨大变化。在动物模型中收集的大量证据表明，绝经后妇女中 NKB 基因表达的增加是继发于卵巢雌激素丧失的。我们假设这些 NKB 神经元在体温调节血管舒张的激活中发挥作用，因此可能参与更年期潮红的产生。我们现在已经收集了大量的试验数据来支持这一假设，并有证据表明存在一种新的神经回路，雌激素的撤退可以激活散热效应器。我们假设大鼠弓状核中的雌激素反应性 NKB 神经元通过投射到视前正中核 (MnPO) 中表达 NK3 受体的神经元来激活温度调节血管舒张，MnPO 是自主神经功能的重要调节中心。本提案将重点关注这一假设。在具体目标 1 中，我们将使用形态学工具来检查大鼠弓状核中雌激素反应性 NKB 神经元与控制体温调节血管舒张的 CNS 中心之间的关系。具体目标 2 将检验以下假设：MnPO 神经元的 NK3 受体激活会刺激大鼠的散热效应器。具体目标 3 将评估干扰表达 NK3 受体的 MnPO 神经元的功能是否会降低卵巢切除大鼠尾部皮肤温度或改变体温调节轴。具体目标 4 将确定 NK3 受体 mRNA 是否在人 MnPO 的神经元中表达。这些研究将为绝经后女性下丘脑基因表达的变化与热潮红特征的散热机制的不当激活之间的潜在关系提供新的见解。了解潮热的机制对于最终设计适当的疗法至关重要。更年期的一个主要特征是潮热，这被认为是中枢神经系统体温调节障碍。潮热是由雌激素流失引起的，其特征是排除体内热量（散热）的生理系统的不适当激活。尽管潮热可能严重影响许多人的生活质量，但目前尚无安全有效的治疗方法。在我们之前的研究中，我们发现绝经后女性下丘脑中一组表达肽神经激肽 B (NKB) 的神经元表现出基因表达增加。我们假设这些 NKB 神经元在散热的生理机制中发挥作用，因此可能参与潮热的产生。本提案旨在检验这一假设。公共健康相关性：这些研究将是第一个将绝经后妇女下丘脑基因表达的变化与更年期最突出的症状之一联系起来的研究。人们对潮热的机制知之甚少，只有少数实验室研究这个问题的基本生物学。了解潮热的机制将极大地有助于针对这些症状设计适当的治疗方法。