HORMONAL CONTROL OF FEMALE REPRODUCTIVE TRACT

女性生殖道的荷尔蒙控制

基本信息

批准号：
6592355
负责人：
ROBERT M BRENNER
金额：
$ 11.11万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-01 至 2003-04-30
项目状态：
已结题

项目摘要

This research aims to increase our understanding of the stromal-epithelial interactions that mediate the action of steroids in the reproductive tract. Our studies focus on the regulation and effects of specific growth factors, and on specific enzymes called matrix metalloproteinases (MMPs). Our studies have progressed in three main areas. First, we have characterized two novel forms of hepatocyte growth factor (HGF) expressed in the macaque endometrium. These two truncated transcripts of HGF are similar to two variants (HGF/NK1 and HGF/NK2 ) that are reported for the human genome. Northern blot of total RNA from microdissected, estradiol-treated endometrium showed that HGF/SF mRNA was expressed at 10 fold higher levels in the functionalis than in the basalis zone. In situ hybridization confirmed this expression gradient and showed that specific signal was confined to the subepithelial and perivascular stromal cells. Second, we immunocytochemically localized expr ession of two forms of vascular endothelial growth factor (VEGF) receptor, Type I (FLT1) and Type II (flk1/KDR) in the macaque endometrium. FLT1 staining was detected on the endothelial surface of small vessels and muscles of larger spiral arteries. Arterial staining was strongest in monkeys treated with estradiol plus progesterone (E2 + P), suggesting that VEGF may play a role during luteal phase artery growth. KDR staining was also evident in vascular endothelial cells. However, when P was withdrawn at the end of the cycle, a wave of strong KDR staining was observed in the stromal cells of the upper functionalis zone. KDR in stromal cells may play a functional role in remodeling the endometrium at the end of the menstrual cycle. Third, a critical period of P withdrawal is required to induce menstruation. We have evaluated expression of various matrix metalloproteinases (MMPs) during and after the critical period. When P is replaced during the critical period, expression of M MP-1, MMP-2, MMP-3, and TIMP 1 are blocked. However, when P is replaced after the critical period, some but not all MMPs are blocked. This indicates that MMPs vary both in their sensitivity to P suppression and their importance in menstruation. FUNDING NIH HD19182 PUBLICATIONS Lindsey JS, Brenner RM. Rhesus macaque endometrium expresses two novel transcripts of hepatocyte growth factor/scatter factor. Biol Reprod (Suppl 1) 58:173 (abstract 324). Lindsey JS, Slayden OD, Brenner RM. A zonal gradient of hepatocyte growth factor/scatter factor expression in rhesus macaque endometrium. Mol Biol Cell 9:477a,1998 (abstract). Rudolph-Owen LA, Slayden OD, Matrisian LM, Brenner RM. Matrix metalloproteinase expression in Macaca mulatta endometrium Evidence for zone-specific regulatory tissue gradients. Biol Reprod 59:1349-1359, 1998.

这项研究旨在加深我们对介导类固醇作用的基质-上皮相互作用生殖道。我们的研究重点是监管和特定生长因子和特定酶的影响基质金属蛋白酶（MMP）。我们的研究取得了进展三个主要领域。首先，我们描述了两种新颖的形式肝细胞生长因子（HGF）在猕猴子宫内膜中表达。 HGF 的这两个截短转录本与两个变体相似（HGF/NK1 和 HGF/NK2）已报告为人类基因组。来自显微切割、雌二醇处理的总 RNA 的 Northern 印迹子宫内膜显示 HGF/SF mRNA 表达高出 10 倍功能区的水平高于基础区。原位杂交证实了这种表达梯度并表明特异性信号仅限于上皮下和血管周围基质细胞。其次，我们通过免疫细胞化学方法进行局部表达两种形式的血管内皮生长因子（VEGF）受体，猕猴子宫内膜中的 I 型 (FLT1) 和 II 型 (flk1/KDR)。 FLT1 在小血管内皮表面检测到染色较大螺旋动脉的肌肉。动脉染色最强的是用雌二醇加孕酮 (E2 + P) 治疗的猴子，表明 VEGF 可能在黄体期动脉生长过程中发挥作用。克德罗血管内皮细胞的染色也很明显。然而，当P周期结束退出时，一波强劲的KDR 在上功能层基质细胞中观察到染色区。基质细胞中的 KDR 可能在重塑中发挥功能性作用月经周期结束时的子宫内膜。三、批判性的需要停药一段时间才能诱发月经。我们有评估各种基质金属蛋白酶 (MMP) 的表达关键期期间和之后。当 P 被替换时关键期，M MP-1、MMP-2、MMP-3 和 TIMP 1 的表达被阻止。然而，当P在关键期后被替换时，一些但并非所有 MMP 都被阻止。这表明 MMP 在以下方面有所不同：他们对 P 抑制的敏感性及其重要性经期。资助 NIH HD19182 出版物 Lindsey JS, Brenner RM。恒河猴子宫内膜表达两种新的转录本肝细胞生长因子/分散因子。生物再现（增补 1）58:173 （摘要 324）。林赛·JS、斯莱登·OD、布伦纳·RM。地带性梯度恒河猴肝细胞生长因子/分散因子表达的影响猕猴子宫内膜。 Mol Biol Cell 9：477a，1998（摘要）。鲁道夫-欧文 LA、斯莱登 OD、Matrisian LM、布伦纳 RM。矩阵猕猴子宫内膜中金属蛋白酶的表达证据用于特定区域的调节组织梯度。生物再现 59：1349-1359，1998。