The role of neurokinin B in the generation of menopausal flushes

描述(申请人提供)：更年期最突出的症状之一是潮热，这是一种中央下丘脑体温调节的紊乱。尽管受到影响的个体数量空前，但人们对潮红的病因知之甚少，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，包括协调激活散热的生理机制(皮肤血管扩张、出汗和行为变化)。整合下丘脑的体温调节和生殖控制中心可能是潮红机制中的一个关键因素。在我们以前的研究中，我们描述了绝经后妇女漏斗(弓状)核中含有雌激素受体的NKB mRNA神经元的形态和基因表达的急剧变化。在动物模型中收集的大量证据表明，绝经后妇女NKB基因表达的增加是卵巢雌激素丢失的次要原因。我们推测，这些NKB神经元在激活体温调节性血管扩张中发挥作用，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说，并有证据表明存在一种新的神经回路，通过这种回路，雌激素撤除可以激活散热效应。我们推测，大鼠弓状核中雌激素反应的NKB神经元通过投射到视前正中核(MnPO)NK3受体表达的神经元来激活温度调节性血管扩张，视前核是自主神经功能的重要调节中心。本提案将侧重于这一假设。在具体目标1中，我们将使用形态学工具来研究大鼠弓状核内雌激素反应的NKB神经元与控制热调节性血管扩张的中枢神经系统之间的关系。特定目的2将验证这样的假设，即激活MnPO神经元的NK3受体刺激大鼠的散热效应。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去卵巢大鼠的尾部皮肤温度或改变体温调节轴。特异性目标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以潮热为特征的散热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合适的治疗方法至关重要。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的紊乱。潮热是由雌激素丢失引起的，其特征是将热量从体内排出的生理系统不适当地激活(散热)。目前，尽管潮热可能严重影响许多人的生活质量，但目前还没有安全有效的治疗方法。在我们以前的研究中，我们发现一组表达神经激肽B(NKB)的神经元在绝经后妇女的下丘脑中表现出基因表达的增加。我们推测，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。目前的提议旨在检验这一假设。公共卫生相关性：这些研究将首次将绝经后女性下丘脑基因表达的变化与绝经最突出的症状之一联系起来。人们对潮热的机制知之甚少，只有几个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促进针对这些症状的适当治疗方法的设计。

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.