Anti-Mullerian hormone for preserving ovarian function before administration of gonadotoxic therapies or after transplantation of cryopreserved tissue.

抗苗勒氏管激素，用于在性腺毒性治疗前或冷冻组织移植后保留卵巢功能。

• 批准号: 10719540
• 负责人: Daylon J James
• 金额: $ 36.44万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-08 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719540
• 关键词: Acceleration; Acute; Address; Affect; Age; Autologous; Autologous Transplantation; Back; Birth Rate; Blood Vessels; Cancer Survivor; Cell Separation; Cells; Chemotherapy-Oncologic Procedure; Childhood; Chronic; Cortex of ovary; Counseling; Cryopreservation; Cryopreserved Tissue; Disease; Disease remission; Engraftment; Environment; Equilibrium; Excision; Female; Foundations; Freezing; Frequencies; Future; Gene Expression; Goals; Gonadal structure; Graft Survival; Growth; Healthcare; Hematologic Neoplasms; Homeostasis; Hormone use; Human; Iatrogenesis; In Situ; Infertility; Inflammatory; Ischemia; Life; Live Birth; Malignant Neoplasms; Measures; Mediating; Menopause; Messenger RNA; Methods; Molecular; Monitor; Morbidity - disease rate; Mus; Newly Diagnosed; Oocytes; Outcome; Output; Ovarian; Ovarian Hyperstimulation Syndrome; Ovarian Stimulations; Ovarian Tissue; Ovarian tissue cryopreservation; Ovary; Pain; Pathologic; Patient risk; Patients; Perfusion; Phase; Physiology; Premature Menopause; Premature Ovarian Failure; Primordial Follicle; Production; Productivity; Proteins; Quality of life; Recombinants; Repression; Resistance; Risk; Services; Signal Transduction; Site; Source; Stimulus; Survival Rate; Survivors; Techniques; Technology; Therapeutic; Time; Tissue Grafts; Tissue Transplantation; Tissue Viability; Tissues; Transplant Recipients; Transplantation; Uncertainty; Vascular Endothelial Cell; Woman; Work; Xenograft procedure; cancer cell; cancer therapy; care burden; cell injury; chemotherapeutic agent; chemotherapy; experimental study; fertility preservation; girls; graft function; improved; improved outcome; inflammatory milieu; mortality; mullerian-inhibiting hormone; ovarian reserve; ovary transplantation; patient population; post-transplant; preconditioning; premature; prepuberty; preservation; protective effect; repository; reproductive; restoration; side effect; stem; tissue processing; young woman

Abstract A frequent side effect of chemotherapy is infertility and female patients newly diagnosed with cancer or other malignancies are routinely counseled to undergo controlled ovarian hyper-stimulation as a means of fertility preservation. For pre-pubertal girls or women requiring immediate chemotherapy, ovarian hyperstimulation is unavailable and many of these patients opt to cryopreserve ovarian tissue with subsequent auto-transplantation once in remission. The increasing frequency of ovarian tissue cryopreservation (OTC) portends a surge in future demand for auto-transplantation, yet the viability/function of grafts is significantly undermined by post-transplant ischemia. Moreover, the iatrogenic influence of chemotherapeutic agents and/or the inflammatory milieu present following tissue auto- transplantation upsets the inter-follicular homeostasis that governs healthy ovarian physiology. We have developed an approach that utilizes cultured vascular cells to accelerate perfusion of transplanted ovarian tissue. In addition, we have demonstrated the potential for an ovary-specific secreted factor, anti-Müllerian hormone (AMH), to modulate follicular growth and activation. The goals of this proposal are to combine these technologies to enhanced tissue viability and follicular output in the context of auto-transplantation and/or mitigate the negative influence of chemotherapeutic agents on the ovary in situ. The proposal aims to address this burgeoning unmet need by: 1) improving viability and output of ovarian tissue grafts by co- transplanting patient-matched vascular endothelial cells isolated at the time of OTC; 2) manipulating signaling within the graft site at the time of ovarian tissue transplantation to repress premature follicular mobilization; and 3) mitigating the gonadotoxic influence of alkylating chemotherapy via pre-conditioning of ovarian tissue with AMH. In pursuing these goals, the proposal stands to improve outcomes for thousands of women who have undergone or will undergo OTC, while also aiming to forego in future patients the risk, expense, pain, and uncertainty of OTC and auto-transplantation.

摘要