SUBCUTANEOUS ENDOMETRIAL AUTOGRAFTS

皮下自体子宫内膜移植物

• 批准号: 2206693
• 负责人: ROBERT M BRENNER
• 金额: $ 15.89万
• 依托单位: OREGON REGIONAL PRIMATE RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2206693
• 关键词: Macaca mulatta; autologous transplantation; biological models; biopsy; collagenase; cytokine; disease /disorder model; endometrium; hormone regulation /control mechanism; hypoxia; immunocytochemistry; in situ hybridization; menstrual cycle; metalloendopeptidases; model design /development; northern blottings; stromelysin; tissue inhibitor of metalloproteinases

The overall goal of this proposal is to utilize subcutaneous endometrial autotransplants in rhesus macaques as a model system for study of the factors that induce menstruation. Once established, these grafts can exhibit histological organization with regional differentiation analogous to the intact endometrium, including the presence of spiral arteries. Estrogen and progestin receptors in the grafts are present and regulated normally. The grafts menstruate in synchrony with the in situ uterus, and express matrilysin (a matrix metalloproteinase) similarly to the eutopic endometrium. Grafts can be sampled in series from the same animal during hormonally induced menses. In preliminary work with the whole macaque uterus we studied the hormonal regulation of seven endometrial matrix metalloproteinases (MMPs) around the time of menstruation. All MMPs were elevated either before or during menses, and all declined subsequent to menses, well before the onset of the luteal phase. P withdrawal led to menses and the upregulation of MMPs whether E2 was present or not, and the MMPs declined spontaneously in the absence of any added P. Consequently we hypothesize the following: P-withdrawal at the end of the menstrual cycle leads to local hypoxia due to spiral artery constriction which "injures" the endometrium and leads to increases in cytokines (and/or other mediators) that in turn lead to induction of the MMPs, which participate in the destruction of the extra cellular matrix and weakening of vascular structural integrity that are associated with menses. As menses ends and the endometrial surface heals, the cytokines and other factors would decline, and this would in turn lead to the decline in MMPs. The following specific aims are proposed to explore this hypothesis in subcutaneous endometrial autografts. 1. Examine hormonal regulation and cellular distribution of MMPs in subcutaneous endometrial autografts during induced menses. 2. Examine hormonal regulation and cellular distribution of various cytokines in subcutaneous endometrial autografts during induced menses. 3. Experimentally test the hypothesis that MMPs identified in Aim 1 or cytokines identified in Aim 2 effect menstrual breakdown by intragraft injection/infusion of MMP or cytokine inhibitors.

该提案的总体目标是利用皮下子宫内膜 恒河猕猴中的自动载植物作为研究模型系统 诱导月经的因素。建立后，这些移植物可以 与区域分化的展览组织学组织类似 到完整的子宫内膜，包括螺旋动脉的存在。 存在移植物中的雌激素和孕激素受体并调节 通常情况下。移植物月经与原位子宫同步， 表达基质蛋白（基质金属蛋白酶）类似 子宫内膜。可以在 荷尔蒙引起的月经。在整个猕猴的初步工作中 子宫我们研究了七个子宫内膜基质的激素调节 月经时期的金属蛋白酶（MMP）。所有MMP都是 在月经之前或期间提升，然后在 月经，在黄体阶段开始之前。 p退出导致 月经和MMP的上调是否存在E2， 在没有任何添加的情况下，MMP自发下降。因此，我们 假设以下内容：月经周期结束时的p-withDrawal 由于螺旋动脉收缩而导致局部缺氧，这会受到“伤害” 子宫内膜并导致细胞因子增加（和/或其他 调解员）反过来导致参与MMP的诱导 在破坏额外的蜂窝基质和血管的削弱中 与月经相关的结构完整性。当月经结束时 子宫内膜表面愈合，细胞因子和其他因素将 下降，这反过来会导致MMP的下降。下列 提出了具体目的，以探讨皮下的这一假设 子宫内膜自体移植。 1。检查激素调节和细胞 在诱导过程中，MMP在皮下子宫内膜自体移植中的分布 月经。 2。检查激素调节和细胞分布 诱导过程中皮下子宫内膜自体移植中的各种细胞因子 月经。 3。实验检验AIM中MMP的假设 AIM 2中鉴定的1或细胞因子通过 MMP或细胞因子抑制剂的内部注射/输注。