Methods of fertility protection by Mullerian inhibiting substance in the female reproductive tract during chemotherapy

项目摘要/摘要： 化疗药物的治疗不仅对女性生育力有持久的影响，而且 也对正常的荷尔蒙动态平衡有影响，因为它会引发提前绝经。化疗药物 对那些太小而不能将胚胎或卵子冷冻作为 保留生育能力的选择。目前还没有既能保护卵巢又能保护卵巢的治疗方法。 维持长期的荷尔蒙功能。我们最近证明了穆勒式 抑制物质(MIS)是一种强大的卵巢抑制药，对卵巢和卵巢都有保护作用 和子宫抵抗化疗的损害。然而，保护机制 这些器官中有哪些是由MISs造成的，目前尚不清楚。我们的长期目标是了解 化疗会损害生育能力，而卵巢中的不孕症又会引发哪些保护途径？ 和子宫。这些发现可能会促进新药的开发，这些新药可以保护 接受化疗的女性患者的生育和内分泌功能。我们 假设心肌梗死或其受体激动剂可以保护卵巢储备，防止 子宫难产，降低早产卵巢功能不全的风险 化疗。我们的理论基础是，MI是唯一已知的能够阻断 原始卵泡激活，因此了解这一途径可以识别一种全新的 治疗靶点的类别。我们的具体目标将检验以下假设：1)管理信息系统 通过抑制原始卵泡激活和颗粒来保护卵巢免受化疗的影响 细胞凋亡；2)微球蛋白通过调控预防阿霉素所致的宫内难产 子宫组织修复；以及3)新发现的MIS受体激动剂可以被证明 在接受化疗的小鼠中保持生育能力。 建议的研究对我们了解 微囊藻毒素在精子保护中的作用机制，具有重要的临床应用潜力。 此外，它们将为卵泡休眠的机制提供新的见解，卵泡休眠是 生殖生物学遗留下来的最大谜团。这些研究具有很高的创新性， 首次提供了对化疗如何损害人类健康的全面评估 卵巢和子宫通过利用单细胞转录获得的单细胞分辨率。 因此，MIS及其小分子类似物可能提供一种新的避孕药范例， 可以保护女性化疗患者的卵巢和子宫功能。

Project summary/Abstract: Treatment with chemotherapeutic agents can have lasting effects not only on female fertility, but also on normal hormonal homeostasis, by triggering premature menopause. Chemotherapeutics can be particularly devastating to girls who are too young to have embryo or egg freezing as a fertility-preserving option. Currently no treatment exists which can both protect the ovaries in situ, and maintain long-term hormonal function. We have recently demonstrated that Mullerian Inhibiting Substance (MIS) is a powerful ovarian suppressant which can protect both the ovary and the uterus against the damages of chemotherapy. However, the mechanisms of protection of these organs by MIS remain unknown. Our long-term goal is to understand how chemotherapy damages fertility, and which protective pathways are elicited by MIS in the ovary and uterus. These discoveries could facilitate the development of novel drugs that can protect both fertility and endocrine function in female patients undergoing chemotherapy. We hypothesize that MIS, or agonists of its receptor, can protect the ovarian reserve, prevent uterine dystocia, and reduce the risk of premature ovarian insufficiency associated with chemotherapy. Our rationale is that MIS is the only known hormone capable of blocking primordial follicle activation, and thus understanding this pathway could identify an entirely new class of therapeutic targets. Our specific aims will test the following hypotheses: 1) that MIS protects the ovary from chemotherapy by inhibiting primordial follicle activation and granulosa cell apoptosis; 2) that MIS prevents uterine labor dystocia caused by doxorubicin by modulating uterine tissue repair; and 3) that newly identified agonists of the MIS receptor can be shown to preserve fertility in mice treated with chemotherapy. The proposed studies represent a significant contribution to our understanding of the mechanisms of action of MIS in fertoprotection, with a potential for significant clinical impact. Furthermore, they will provide novel insights into the mechanism of follicle dormancy, one of the greatest remaining mysteries of reproductive biology. These studies are highly innovative by providing for the first time a comprehensive assessment of how chemotherapy damages the ovary and uterus at the single cell resolution through the use of single cell transcriptomics. Thus, MIS and its small molecule analogs may provide a novel paradigm of a contraceptive that can protect both ovarian and uterine function in female patients undergoing chemotherapy.