The role of neurokinin B in the generation of menopausal flushes

描述（由申请人提供）：更年期最突出的症状之一是潮热，这是一种下丘脑中枢体温调节紊乱。尽管受影响的个体数量空前，但对潮红的病因知之甚少，很少有实验室在研究这种现象的基本生物学。潮热是由雌激素退出引起的，由协调激活的生理机制来散热（皮肤血管扩张，出汗和行为改变）。下丘脑控制中心对体温调节和生殖的整合可能是脸红机制的关键因素。在我们之前的研究中，我们描述了绝经后妇女的弓状核中含有雌激素受体的含有NKB mRNA的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NKB基因表达的增加是继发于卵巢雌激素的丧失。我们假设这些NKB神经元在热调节血管舒张的激活中起作用，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点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。我们假设大鼠弓形核中的雌激素反应性NKB神经元通过投射到中视前核（MnPO）中表达NK3受体的神经元来激活热调节性血管舒张，中视前核是自主神经功能的重要调节中心。本建议将着重于这一假设。在具体目标1中，我们将使用形态学工具来研究大鼠弓形核中雌激素反应性NKB神经元与控制热调节血管舒张的中枢神经系统中心之间的关系。特异性目的2将验证NK3受体激活MnPO神经元刺激大鼠散热效应的假设。特异性目的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热调节轴。特异性靶4将确定NK3受体mRNA是否在人类MnPO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潮热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。潮热是由雌激素的丧失引起的，其特征是生理系统的不适当激活，这些生理系统将热量从体内排出（散热）。目前，尽管潮热可能严重影响许多人的生活质量，但还没有安全有效的治疗方法。在我们之前的研究中，我们发现一组表达神经肽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更年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本生物学。了解潮热的机制将极大地促进设计适当的治疗这些症状。

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.