STEROID HORMONE REGULATION OF ANGIOGENESIS IN ENDOMETRIUM--IMPACT ON FERTILITY

类固醇激素对子宫内膜血管生成的调节——对生育力的影响

• 批准号: 6318368
• 负责人: Eugene D. Albrecht
• 金额: $ 13.96万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6318368
• 关键词: Adenoviridae; angiogenesis; antisense nucleic acid; baboons; cell differentiation; cooperative study; endometrium; estradiol; estrogens; female; fertility; fibroblast growth factor; gene expression; growth factor receptors; hormone regulation /control mechanism; human tissue; membrane permeability; menstrual cycle; progesterone; steroid hormone; tissue /cell culture; transfection; vascular endothelial growth factors

The uterine endometrium undergoes extensive cellular differentiation and development of new blood vessels, i.e. angiogenesis during each menstrual cycle in preparation for implantation. Although estrogen and progesterone have established role in neovascularization, the mechanisms underlying this process have not been established. Specific growth-promoting peptides, i.e. vascular endothelial growth/permeability factor (VEG/PF) and basic fibroblast growth factor (bFGF), stimulate angiogenesis in other systems. Therefore, the present combined basic-clinical research project will utilize in vivo approaches in an established non-human primate model, the baboon, and a microcarrier-based cocultivation system with human endometrial cells to test the hypothesis that estrogen and/or progesterone regulate angiogenesis with the endometrium by stimulating expression of VEG/PR and bFGF and their receptors. In Study 1, angiogenesis, microvascular permeability and expression and cellular localization of VEG/PF and bFGF and their respective tyrosine kinase receptors will be determined in baboons during the normal menstrual cycle and after ovariectomy and the acute or chronic administration of estradiol and/or progesterone. Study 2 will employ an adenovirus-mediated antisense oligonucleotide transfer approach to disrupt the expression of VEG/PF and bFGF in the uterus to test in vivo the hypothesis that these peptides have essential roles upon angiogenesis within the endometrium and consequently upon fertility of the baboon. Study 3 will use a microcarrier cocultivation system to test the hypothesis that estrogen and/or progesterone regulate angiogenesis in human endometrial cells by simulating expression of VEG/PF and bFGF and their receptors. The objective of this study is to transfer the knowledge gained on the physiology and regulation of the angiogenesis system in vivo in the baboon to the study of human endometrial cells in vitro. Completion of this project will provide a fundamental basis for improving our understanding of the etiology of, and establishing in future project years more effective hormonal treatment modalities for, infertility in women.

子宫子宫内膜经历广泛的细胞分化和 新血管的发展，即每次月经期间的血管生成 循环为植入准备。虽然雌激素和孕激素 已经在新血管形成中确立了作用， 这个过程尚未建立。特定的增长促进 肽，即血管内皮生长/渗透率因子（VEG/PF） 和碱性成纤维细胞生长因子（BFGF），刺激其他血管生成 系统。因此，目前的基础临床研究项目 将在已建立的非人类灵长类动物模型中使用体内方法， 狒狒和基于微载体的共培养系统与人类 子宫内膜细胞测试雌激素和/或孕酮的假设 通过刺激表达来调节子宫内膜的血管生成 VEG/PR和BFGF及其受体。在研究1中，血管生成， 微血管通透性，表达和细胞定位 VEG/PF和BFGF及其各自的酪氨酸激酶受体将是 在正常月经周期和之后在狒狒中确定 卵巢切除术以及雌二醇和/或急性或慢性给药 孕酮。研究2将采用腺病毒介导的反义 寡核苷酸转移方法破坏了VEG/PF的表达 子宫中的BFGF在体内测试这些肽具有的假设 子宫内膜内血管生成的基本作用，因此 狒狒的生育能力。研究3将使用微载体 共培养系统测试雌激素和/或的假设 孕酮调节人子宫内膜细胞的血管生成 模拟VEG/PF和BFGF及其受体的表达。这 这项研究的目的是转移有关获得的知识 狒狒体内血管生成系统的生理和调节 在体外研究人子宫内膜细胞。完成此操作 项目将为提高我们的理解提供基本的基础 的病因和在未来项目中建立更多 女性不育症的有效荷尔蒙治疗方式。