A macaque model for endometriosis induced pelvic pain and infertility

子宫内膜异位症引起的盆腔疼痛和不孕症的猕猴模型

• 批准号: 8666680
• 负责人: OV D SLAYDEN
• 金额: $ 20.8万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-27 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666680
• 关键词: Abdominal Cavity; Animal Disease Models; Animal Model; Animals; Assisted Reproductive Technology; Atypia; Cervix Uteri; Clinical Trials; Curettage procedure; Data; Development; Disease; Disease Progression; Drug Industry; Endometrial; Endometrium; Failure; Fertility; Functional disorder; Future; Goals; Growth; Hormonal; Housing; Infertility; Investigation; Laboratories; Lesion; Macaca; Macaca mulatta; Masks; Medical; Menstrual cycle; Methods; Modeling; Monitor; Monkeys; Morphology; Movement; Needles; Ovarian; Ovarian Steroid Hormone; Pain; Pain Measurement; Papio; Partner in relationship; Pathogenesis; Pattern; Pelvic Pain; Pelvis; Peritoneal; Peritoneum; Pilot Projects; Positioning Attribute; Pregnancy; Primates; Progesterone; Protocols documentation; Public Health; Reproductive Biology; Research; Research Institute; Resistance; Role; Sigmoid colon; Site; Sleep; Staging; Sum; System; Techniques; Testing; Time; Tissues; Translations; Transplantation; Ultrasonography; Uterine cavity; Woman; Women' s Health; Work; animal colony; animal resource; base; cost; design; endometriosis; in vivo; inflammatory marker; male; natural Blastocyst Implantation; nonhuman primate; novel therapeutic intervention; research study; response; tool

DESCRIPTION (provided by applicant): Endometriosis is a painful disorder for millions of women. Progress on new therapeutic approaches for endometriosis has been slow because there are limited physiologically relevant animal models for the disease. Nonhuman primates (NHPs) constitute the most suitable animals for in vivo studies, and creating endometriosis by inoculating endometrial currettings to the abdominal cavity of the baboon is the prototypic primate model. However, research in baboons is grossly limited by animal availability, cost, and housing constraints for large NHPs. In contrast, macaques are the preferred NHP in many research institutes and the pharmaceutical industry, and therapies evaluated in the macaque would be well-positioned for translation to clinical trials. Several studies have created ectopic endometrium in macaques, those studies failed to yield a reliable endometriosis model. Those failures appear technological and we propose that a reliable macaque endometriosis model can be created that will have a lasting impact on women's health. In Specific Aim 1 we will refine and validate a protocol for creating endometriosis in naturally cycling macaques. Curettage, as used in baboons, cannot be carried out in macaques because of anatomical restrictions in the macaque cervix. To overcome this, we will collect menstrual endometrium debris by needle aspiration and transfer it to the abdominal cavity laparoscopically. Enthusiasm for Aim 1 emanates from pilot studies where we inoculated the peritoneum with menstrual endometrium in artificially-cycled monkeys. In Specific Aim 2 we will document the growth of induced endometriotic lesions and assess the effects of lesion abundance and size on the presentation of pain in the animals. Based on our pilot data we designed a pain and discomfort scoring system, which will be combined with activity monitoring, to quantify discomfort in animals with induced disease and guide the prescription of pain relief for the animals. Objective data on pain, sleep, and activity will be used for scoring pain throughout the menstrual cycle in animals with induced endometriosis. Like women, NHPs with endometriosis are expected to display reduced fertility compared to endometriosis-free subjects. In Specific Aim 3 we will assess the effect of the induced lesions on fertility. Fertility will be assessed by mating the animals with fertile mals. Pelvic ultrasound and contrast enhanced ultrasound imaging will be used to characterize the effects of induced endometriosis on uterine function and embryo implantation. This research will provide a definitive assessment of techniques required to create endometriosis in the macaque for future studies, and characterize the progression of the disease with specific emphasis on assessment of pain and infertility in this useful NHP model.

描述（由申请人提供）：子宫内膜异位症对数百万女性来说是一种痛苦的疾病。子宫内膜异位症的新治疗方法进展缓慢，因为该疾病的生理相关动物模型有限。非人灵长类动物（NHP）是最适合体内研究的动物，通过将子宫内膜接种到狒狒腹腔中产生子宫内膜异位症是灵长类动物模型的原型。然而，狒狒研究受到动物可用性、成本和大型 NHP 住房限制的严重限制。相比之下，猕猴是许多研究机构和制药行业首选的 NHP，在猕猴身上评估的疗法将有利于转化为临床试验。几项研究在猕猴中建立了异位子宫内膜，但这些研究未能产生可靠的子宫内膜异位症模型。这些失败似乎是技术性的，我们建议可以创建一个可靠的猕猴子宫内膜异位症模型，这将对女性的健康产生持久的影响。在具体目标 1 中，我们将完善并验证在自然循环猕猴中产生子宫内膜异位症的方案。由于猕猴子宫颈的解剖学限制，不能对狒狒进行刮宫术。为了克服这个问题，我们将通过针吸收集月经子宫内膜碎片，并通过腹腔镜将其转移到腹腔。对目标 1 的热情源于试点研究，我们在人工周期猴子的腹膜上接种了月经子宫内膜。在具体目标 2 中，我们将记录诱发的子宫内膜异位病变的生长，并评估病变丰度和大小对动物疼痛表现的影响。根据我们的试点数据，我们设计了一个疼痛和不适评分系统，该系统将与活动监测相结合，以量化患有诱发疾病的动物的不适并指导动物的疼痛缓解处方。关于疼痛、睡眠和活动的客观数据将用于对诱发子宫内膜异位症的动物整个月经周期的疼痛进行评分。与女性一样，与无子宫内膜异位症的受试者相比，患有子宫内膜异位症的 NHP 预计会表现出生育能力下降。在具体目标 3 中，我们将评估诱发病变对生育力的影响。通过将动物与有生育能力的雄性交配来评估生育能力。盆腔超声和对比增强超声成像将用于表征诱发子宫内膜异位症对子宫功能和胚胎植入的影响。这项研究将对在猕猴中产生子宫内膜异位症所需的技术进行明确的评估，以供未来的研究使用，并描述疾病的进展特征，特别强调在这个有用的 NHP 模型中评估疼痛和不孕症。