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

化疗期间女性生殖道苗勒氏管抑制物质保护生育力的方法

• 批准号: 10560626
• 负责人: David Pepin
• 金额: $ 36.14万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560626
• 关键词: Acceleration; Address; Agonist; Apoptosis; Blood Vessels; Cancer Patient; Cancer Survivor; Carboplatin; Cells; Chemotherapy and/or radiation; Clinical; Contraceptive Agents; Cyclophosphamide; Development; Doxorubicin; Endocrine; Endometrial; Feedback; Female; Fertility; Fibrosis; GNRH1 gene; Goals; Growing Follicle; Homeostasis; Hormonal; Hormones; Human; In Situ; Infertility; Labor Dystocia; Life; Low Birth Weight Infant; Malignant Neoplasms; Medical; Methods; Mullerian-inhibiting substance receptor; Mus; Muscle; Organ; Ovarian; Ovary; Paclitaxel; Pathway interactions; Patients; Pelvis; Pharmaceutical Preparations; Premature Birth; Premature Menopause; Primordial Follicle; Property; Radiation; Radiation Toxicity; Recombinants; Reproductive Biology; Reproductive Health; Resolution; Rest; Risk; Risk Reduction; Spontaneous abortion; Survivors; Testing; Therapeutic; Thick; Time; Toxic effect; Toxicity due to chemotherapy; Transgenic Mice; Translating; Treatment outcome; Uterus; Woman; analog; bevacizumab; burnout; cancer therapy; cell type; chemotherapeutic agent; chemotherapy; clinical care; clinical development; design; drug candidate; drug repurposing; embryo cryopreservation; female fertility; fertility preservation; gemcitabine; girls; granulosa cell; improved outcome; innovation; insight; mimetics; mouse model; mullerian-inhibiting hormone; myometrium; novel; novel therapeutics; oocyte cryopreservation; ovarian damage; ovarian reserve; paracrine; prevent; primary ovarian insufficiency; progenitor; protective effect; protective pathway; receptor; recruit; repaired; reproductive tract; response; single-cell RNA sequencing; small molecule; standard of care; therapeutic target; tissue repair; transcriptomics; young woman

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.

项目概要/摘要： 化疗药物治疗不仅对女性生育能力产生持久影响，而且对女性生育能力产生持久影响。 还通过引发过早更年期来影响正常的荷尔蒙稳态。化疗 对于年龄太小而无法冷冻胚胎或卵子的女孩来说，这可能尤其具有毁灭性 保留生育能力的选择。目前尚无既能保护卵巢又能保护卵巢的治疗方法 原位，并维持长期的荷尔蒙功能。我们最近证明了苗勒管 抑制物质（MIS）是一种强大的卵巢抑制剂，可以保护卵巢 以及子宫抵抗化疗的损害。然而，保护机制 MIS 对这些器官的影响仍然未知。我们的长期目标是了解如何 化疗损害生育能力，MIS 在卵巢中引发哪些保护途径 和子宫。这些发现可以促进新药的开发，以保护 接受化疗的女性患者的生育功能和内分泌功能。我们 假设 MIS 或其受体激动剂可以保护卵巢储备、预防 子宫难产，并降低与卵巢早衰相关的风险 化疗。我们的理由是，MIS 是唯一已知能够阻断 原始卵泡激活，从而了解该途径可以识别一个全新的 治疗靶点类别。我们的具体目标将检验以下假设：1）MIS 通过抑制原始卵泡活化和颗粒来保护卵巢免受化疗的影响 细胞凋亡； 2) MIS通过调节预防多柔比星引起的子宫难产 子宫组织修复； 3) 新鉴定的 MIS 受体激动剂可以证明 保留接受化疗的小鼠的生育能力。 拟议的研究对我们理解这一问题做出了重大贡献 MIS 在生育保护中的作用机制，具有潜在的重大临床影响。 此外，他们将为卵泡休眠机制提供新的见解，卵泡休眠是休眠的机制之一。 生殖生物学中最大的未解之谜。这些研究极具创新性 首次对化疗如何损害细胞进行全面评估 通过使用单细胞转录组学以单细胞分辨率观察卵巢和子宫。 因此，MIS 及其小分子类似物可能提供一种新的避孕方法 可以保护接受化疗的女性患者的卵巢和子宫功能。