DISRUPTION OF OVULATION OR LUTEAL DEVELOPMENT W/ ANTI ANGIOGENIC AGENTS

使用抗血管生成药物破坏排卵或黄体发育

• 批准号: 6453708
• 负责人: RICHARD L STOUFFER
• 金额: $ 11.11万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6453708
• 关键词: Mammalia; animal tissue; cardiovascular system; clinical research; endocrine gland /system; hormones; model design /development; mother /infant health care; pharmacology; reproductive system; technology /technique; women's health

Recent advances were made in understanding the processes that regulate the development, maintenance and remodeling of the vasculature in tissues. These concepts are relevant to the control of reproduction since normal angiogenesis in adults is almost exclusively limited to cyclic changes in the ovary and reproductive tract. Notably, the periovulatory events of follicle rupture and conversion of the follicle into the corpus luteum involve remarkable changes in vascular permeability and neovascularization of the granulosa layer destined to form luteal tissue. Thus, agents that disrupt these vascular processes could suppress the gamete (oocyte) or hormonal (i.e., progesterone) components necessary for fertility and intrauterine implantation. To test this hypothesis, experiments were initiated in a nonhuman primate model, the rhesus monkey, to (Aim No. 1) determine if two categories of anti-angiogenic agents, a general angiostatic compound (AGM-1470) and a specific anti -vascular endothelial growth factor (anti-VEGF), block ovulation or impair the development/function of the corpus luteum of the menstrual cycle. Either vehicle or drug will be injected directly into the preovulatory follicle (day 0 to 1 post-gonadotropin surge). In phase one, laparoscopic evaluation and analyses of steroid levels in daily serum samples will evaluate follicle rupture and the function/lifespan of the corpus luteum. In phase two, hemiovariectomy 4 days after injection will provide tissues for morphometric, immunocytochemical and molecular analyses of the developing corpus luteum, including its vasculature. Experiments are also planned (Aim No. 2) to establish the specificity of action of anti-angiogenic agents in the primate ovary. Although these drugs are proposed to act specifically on vascular endothelial cells, it is important to determine if there are effects on other ovarian cell types. Finally, to determine if there are any extra-ovarian effects due to drug that reaches the reproductive tract, histologic and morphometric analyses of uterine biopsies will be performed. It is expected that a working dose for at least one anti-angiogenic agent may be defined for further preclinical trials evaluating its potential via systemic administration as a novel contraceptive acting to block ovulation and/or implantation. FUNDING World Health Organization (RF96020 #75), NIH HD22408 PUBLICATIONS None

在理解的过程中取得了最新进展 规范的开发，维护和重塑 组织中的脉管系统。 这些概念与控制 繁殖，因为成年人的正常血管生成几乎完全是 仅限于卵巢和生殖道的循环变化。 值得注意的是，卵泡破裂和转化的卵巢周围事件 卵泡中的叶片叶片涉及显着的变化 颗粒层的血管渗透性和新血管形成 注定形成黄体组织。 因此，破坏这些的代理商 血管过程可以抑制配子（卵母细胞）或激素 （即孕酮）生育所需的成分 宫内植入。 为了检验该假设，实验是 在非人类灵长类动物模型The Rhesus Monkey中发起的（目标编号 1）确定两类抗血管生成剂是否是一般的 血管静态化合物（AGM -1470）和特定的抗血管 内皮生长因子（抗VEGF），阻断排卵或损害 月经周期的Luteum的发展/功能。 媒介物或药物将直接注射到预防前 卵泡（第0天至第1天，冈多尔蛋白激增）。 在第一阶段， 腹腔镜评估和每日血清类固醇水平的分析 样品将评估卵泡破裂和功能/寿命 Luteum。 在第二阶段，半伏雄切除术后4天 注射将提供形态计量学，免疫细胞化学的组织 以及对发育中的Luteum的分子分析，包括其 脉管系统。 还计划了实验（目标2）以建立 抗血管生成剂在灵长类动物中的作用特异性 子房。 尽管建议这些药物专门起作用 血管内皮细胞，重要的是确定是否存在 对其他卵巢细胞类型的影响。 最后，确定是否在那里 是否由于药物而导致的任何卵巢外影响 子宫的生殖道，组织学和形态分析 活检将进行。 预计可以使用的剂量 至少可以将一种抗血管生成剂定义用于进一步的临床前 试验通过全身管理评估其潜力作为一种新颖 避孕作用以阻止排卵和/或植入。 资金 世界卫生组织（RF96020＃75），NIH HD22408出版物无