Sex Steroid Hormones and Calcitonin Gene-Related Peptide

描述(申请人提供)：肌松药分子为 与妊娠期间血管适应的调节有关 子宫胎盘功能正常，胎儿生长发育正常。我们的长期目标是 研究是为了确定强效的平滑肌松弛剂降钙素的作用 基因相关肽(CGRP)在这些血管适应和子宫胎盘中的作用 功能。在前一个资助期，我们发现两者的表达 CGRP及CGRP的血管扩张作用在妊娠期和 受性类固醇激素影响。然而，降钙素基因相关肽诱导血管扩张的机制 以及CGRP在子宫和胎盘血流中的作用 监管是未知的。因此，此应用程序的总体目标是 降钙素基因相关肽对肠系膜动脉血管松弛作用机制的研究 并探讨CGRP在大鼠子宫胎盘血流中的作用。 需要检验的假设是：1)降钙素基因相关肽诱导的肠系膜增厚 妊娠期动脉松弛与降钙素基因相关肽表达升高有关 受体成分、组织降钙素受体样受体和受体 信号修饰蛋白(RAMP1)及其受体后信号转导，2) 降钙素基因相关肽参与子宫胎盘血流和胎儿的调节 成长。提出了三个具体目标。具体目标1：确定CGRP的特征 肠系膜动脉的受体和受体后信号转导，并描述 大鼠妊娠期间受体的调节及性激素的作用 荷尔蒙。我们将测量CRLR和RAMP1，即受体后信号的变化 和肠系膜动脉的松弛，并评估CGRP诱导的血液 并评估性类固醇激素对它们的调节作用。 特定目的2：观察降钙素基因相关肽对子宫动脉的扩张作用 并评估这些影响是否受怀孕和性激素的调节 荷尔蒙。我们将测量CRLR、RAMP1和受体后信号的变化 和子宫动脉的松弛，并评估CGRP诱导的血流量 妊娠和类固醇激素的调节。具体目标3：调查 降钙素基因相关肽在胎盘血流中的作用我们将衡量CRLR的变化， RAMP1和CGRP在妊娠晚期胎盘中的结合及其意义 性激素的影响及评价CGRP诱导的血流量 胎盘。这些研究将有助于评估降钙素基因相关肽在血管中的作用 在妊娠期间的适应和胎儿的生长发育，并为 探讨降钙素基因相关肽在妊娠中的治疗价值。

DESCRIPTION (provided by applicant): Smooth muscle relaxant molecules are implicated in the regulation of vascular adaptations during pregnancy and in normal uteroplacental function and fetal growth. The long-term goal of our research is to define the role of potent, smooth muscle relaxant, calcitonin gene-related peptide (CGRP) in these vascular adaptations and uteroplacental function. In the previous funding period, we found that both the expression of CGRP and the vasodilatory action of CGRP are upregulated during pregnancy and by sex-steroid hormones. However, the mechanisms of CGRP-induced vasodilation as well as the involvement of CGRP in uterine and placental blood flow regulation are not known. Thus, the overall goal of this application is to determine the mechanisms of CGRP-induced vasorelaxation of mesenteric artery and assess the involvement of CGRP in uteroplacental blood flow in the rat. Hypotheses to be tested are: 1) that the increased CGRP-induced mesenteric artery relaxation during pregnancy is due to elevated expression of CGRP receptor components, caicitonin receptor-like receptor (CRLR) and receptor signaling modifying protein (RAMP1), and their post-receptor signaling, and 2) CGRP is involved in the regulation of uteroplacental blood flow and fetal growth. Three specific aims are proposed. Specific aim 1: to characterize CGRP receptors and post-receptor signaling in the mesenteric artery and describe the regulation of the receptors during rat pregnancy and by the sex-steroid hormones. We will measure changes in CRLR and RAMP1, post-receptor signaling and arterial relaxation of mesenteric artery, and assess CGRP-induced blood flow throughout gestation and assess their regulation by sex-steroid hormones. Specific aim 2: to examine the vasodilatory effects of CGRP on uterine artery and assess if these effects are regulated by pregnancy and sex-steroid hormones. We will measure changes in CRLR, RAMP1 and post-receptor signaling and relaxation of uterine artery, and assess CGRP-induced blood flow throughout gestation and regulation by steroid hormones. Specific aim 3: to investigate the role of CGRP in placental blood flow. We will measure changes in CRLR, RAMP1 and CGRP binding in placenta throughout late gestation and their influence by sex-steroid hormones and assess CGRP-induced blood flow through placenta. These studies would help assess the involvement of CGRP in vascular adaptations and in fetal growth during pregnancy and lay a foundation for assessing therapeutic value of CGRP in pregnancy.