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: 8288748
• 负责人: NAOMI E RANCE
• 金额: $ 26.5万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288748
• 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; Health; 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; Ovarian; Peptides; Physiologic Thermoregulation; Physiological; Play; Postmenopause; 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; 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温度调节障碍。尽管受影响的个体数量前所未有，但对潮红的病因学了解甚少，很少有实验室研究这种现象的基础生物学。潮热是由雌激素戒断引起的，包括协调激活生理机制以散热（皮肤血管舒张、出汗和行为变化）。整合下丘脑的温度调节和生殖控制中心可能是潮红机制的关键因素。在我们以前的研究中，我们描述了绝经后妇女漏斗（弓状）核中含雌激素受体的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基因表达的增加继发于卵巢雌激素的损失。我们假设这些NKB神经元在体温调节血管舒张的激活中起作用，因此可能参与绝经期潮红的产生。我们现在已经收集了大量的试验数据来支持这一假设，并有证据表明一种新的神经回路，即雌激素戒断激活散热效应器。我们推测，雌激素反应性NKB神经元在大鼠弓状核激活体温调节血管舒张通过预测到NK3受体表达神经元的正中视前核（MnPO），一个重要的调节中心自主神经功能。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的雌激素反应性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MnPO神经元的NK3受体激活刺激大鼠中的散热效应器的假设。具体目标3将评估是否干扰NK3受体表达MnPO神经元的功能，降低尾部皮肤温度或改变卵巢切除大鼠的体温调节轴。具体目标4将确定NK 3受体mRNA是否在人MnPO的神经元中表达。这些研究将为绝经后妇女下丘脑基因表达的变化与热耗散机制的不适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治疗至关重要。更年期的一个主要特征是潮热，这被认为是中枢神经系统温度调节的障碍。潮热是由雌激素的损失引起的，其特征是从身体中移除热量的生理系统的不适当激活（散热）。目前，没有安全有效的治疗方法，尽管潮热可能严重影响许多人的生活质量。在我们以前的研究中，我们发现一组表达肽神经激肽B（NKB）的神经元在绝经后妇女的下丘脑中表现出增加的基因表达。我们假设这些NKB神经元在散热的生理机制中起作用，因此可能参与潮热的产生。本提案旨在检验这一假设。公共卫生相关性：这些研究将首次将绝经后妇女下丘脑基因表达的变化与绝经期最突出的症状之一联系起来。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础生物学。了解潮热的机制将大大有助于设计适当的治疗这些症状。