SUPPRESSION OF MENSTRUAL BLEEDING IN RHESUS MACAQUES

抑制恒河猴的月经出血

• 批准号: 8357806
• 负责人: OV D SLAYDEN
• 金额: $ 11.65万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357806
• 关键词: Acute; Blood Vessels; CCL2 gene; Coupled; Endometrium; Epithelial; Funding; Goals; Grant; Hemorrhage; IL8 gene; IL8RB gene; Infiltration; Inflammation; Interleukin-8; Leukocytes; Macaca mulatta; Measurement; Mediating; Medical; Menstrual cycle; Methods; Modeling; Monocyte Chemoattractant Proteins; National Center for Research Resources; Necrosis; Primates; Principal Investigator; Progesterone; Proteins; Research; Research Infrastructure; Resources; Solubility; Source; Testing; United States National Institutes of Health; Withdrawal; Woman; chemokine; chemokine receptor; cost; macrophage; neutrophil; nonhuman primate; receptor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goal is to develop new medical therapies that reduce heavy menstrual bleeding in women. Menstrual bleeding is triggered by an acute decrease in systemic progesterone. Our hypothesis is that progesterone withdrawal triggers local inflammation coupled with the ingress of leukocytes (neutrophils and macrophages), which results in loss of blood vessel integrity, epithelial necrosis and sloughing of the upper layers of endometrium. Leukocyte infiltration is mediated by the local expression of small secreted proteins (chemokines) including interleukin 8 (IL-8; CXCL8) and monocyte chemoattractant protein (MCP-1; CCL-2). Antagonists that block the receptors for IL8 and MCP-1 (CXCR2 and CCR2b) have been developed. Rhesus macaques are menstruating nonhuman primates with menstrual cycles that are very similar to those of women and can provide a model for testing chemokine receptor antagonists (AZ01 and AZ02) on menstrual blood loss (MBL). Our Aims are: Aim 1 is to validate new methods for the measurement of menstrual blood loss in rhesus macaques; Aim 2 is to test the effects of AZ01 and AZ02 on menstrual bleeding in rhesus macaques. We found that AZ01 and AZ02 (20 mg/kg) are well-tolerated, but the effect of AZ01 on MBL was variable, possibly due to the poor solubility of AZ01. Combining AZ01 and AZ02 reduced MBL. We conclude that blockade of inflammation may provide a valuable target for reducing heavy menstrual bleeding.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 其目标是开发新的医学疗法，减少女性大量的月经出血。月经出血是由全身孕酮的急剧下降引起的。我们的假设是，黄体酮停用会引发局部炎症，并伴随着白细胞(中性粒细胞和巨噬细胞)的进入，从而导致血管完整性丧失、上皮坏死和子宫内膜上层塌陷。白介素8(IL-8；CXCL8)和单核细胞趋化蛋白(MCP-1；CCL-2)等小分泌蛋白(趋化因子)的局部表达介导了白细胞的浸润。阻断IL8和MCP-1受体(CXCR2和CCR2b)的拮抗剂已经开发出来。猕猴是非人类灵长类动物，其月经周期与女性非常相似，可以为测试趋化因子受体拮抗剂(AZ01和AZ02)对月经失血(MBL)的影响提供一个模型。我们的目标是：目标1验证恒河猴月经失血量测量的新方法；目标2测试AZ01和AZ02对恒河猴月经出血的影响。我们发现AZ01和AZ02(20 mg/kg)耐受性良好，但AZ01对MBL的影响是不同的，可能是由于AZ01的溶解性差所致。AZ01和AZ02联合应用可降低MBL。我们的结论是，阻断炎症可能为减少大量月经出血提供一个有价值的靶点。