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.

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