A macaque model for endometriosis induced pelvic pain and infertility

描述(申请人提供)：子宫内膜异位症是数百万女性的一种痛苦的疾病。治疗子宫内膜异位症的新方法进展缓慢，因为目前与该疾病生理相关的动物模型有限。非人灵长类动物是最适合进行活体研究的动物，通过将子宫内膜异位物接种到狒狒的腹腔来制造子宫内膜异位症是典型的灵长类动物模型。然而，对狒狒的研究受到动物可获得性、成本和大型NHP的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业的首选NHP，在猕猴身上评估的疗法将非常适合转化为临床试验。有几项研究在猕猴体内制造了异位子宫内膜，但这些研究都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，我们建议可以建立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，我们将完善和验证在自然循环猕猴中创建子宫内膜异位症的方案。由于猕猴宫颈的解剖学限制，刮宫手术不能在猕猴身上进行，就像在狒狒身上使用的那样。为了克服这一点，我们将通过针吸收集月经子宫内膜碎片，并在腹腔镜下将其转移到腹腔。对目标1的热情来自于先导研究，在这些研究中，我们在人工周期猴子的腹膜中接种月经子宫内膜。在特定的目标2中，我们将记录诱发的子宫内膜异位病变的生长情况，并评估病变的丰度和大小对动物疼痛表现的影响。基于我们的试点数据，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，以量化患有诱导性疾病的动物的不适感，并指导动物的止痛处方。目的关于疼痛、睡眠和活动的数据将被用于对诱发子宫内膜异位症动物整个月经周期的疼痛进行评分。与女性一样，患有子宫内膜异位症的NHP与非子宫内膜异位症的受试者相比，生育力预计会降低。在具体目标3中，我们将评估诱导损伤对生育的影响。繁殖力将通过将这些动物与有生育能力的雄性交配来评估。盆腔超声和增强超声成像将被用来表征诱导性子宫内膜异位症对子宫功能和胚胎植入的影响。这项研究将为未来的研究提供对在猕猴中制造子宫内膜异位症所需技术的明确评估，并描述疾病的进展，特别强调在这个有用的NHP模型中评估疼痛和不孕不育。

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.