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: 6440541
• 负责人: Eugene D. Albrecht
• 金额: $ 17.42万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6440541
• 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.

子宫内膜经历广泛的细胞分化 新血管的发育，即每次月经期间的血管生成 周期，为植入做准备。虽然雌激素和孕激素 已在新生血管形成中发挥作用，其机制 这一过程尚未建立。特异性促生长 肽，即血管内皮生长/通透因子（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，目前的基础临床联合研究项目 将在已建立的非人类灵长类动物模型中利用体内方法， 狒狒，以及基于微载体的人类共培养系统 子宫内膜细胞来检验雌激素和/或孕激素的假设 通过刺激子宫内膜的表达来调节血管生成 VEG/PR 和 bFGF 及其受体。在研究 1 中，血管生成， 微血管通透性和表达以及细胞定位 VEG/PF 和 bFGF 及其各自的酪氨酸激酶受体将 狒狒在正常月经周期期间和之后进行测定 卵巢切除术和急性或长期服用雌二醇和/或 黄体酮。研究 2 将采用腺病毒介导的反义序列 寡核苷酸转移方法破坏 VEG/PF 的表达和 bFGF 在子宫中测试体内这些肽具有的假设 对子宫内膜内血管生成的重要作用，因此 狒狒的生育能力。研究 3 将使用微载体 共培养系统来检验雌激素和/或 黄体酮通过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在该研究中获得的知识 狒狒体内血管生成系统的生理学和调节 体外研究人类子宫内膜细胞。完成此 项目将为提高我们的理解提供基础基础 的病因学，并在未来的项目年中建立更多 针对女性不孕症的有效激素治疗方式。