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 化疗的常见副作用是不孕症和新诊断为癌症的女性患者， 其他恶性肿瘤常规建议进行控制性卵巢过度刺激， 保持生育能力对于青春期前女孩或需要立即化疗的妇女，卵巢癌 过度刺激是不可用的，这些患者中的许多选择冷冻保存卵巢组织， 一旦缓解，随后进行自体移植。越来越多的卵巢组织 冷冻保存（OTC）预示着未来对自体移植需求的激增，但 移植物的存活力/功能被移植后局部缺血显著破坏。此外，医源性 化疗剂和/或组织自体移植后存在的炎性环境的影响， 移植扰乱了控制健康卵巢生理学的卵泡间稳态。我们有 开发了一种利用培养的血管细胞来加速移植卵巢灌注的方法， 组织.此外，我们已经证明了卵巢特异性分泌因子抗Mu Eschillerian的潜力， 激素（AMH），以调节卵泡生长和激活。本提案的目标是将联合收割机 这些技术在自体移植的背景下提高了组织活力和卵泡产量 和/或减轻化疗剂对卵巢原位的负面影响。该提案旨在 为了解决这一新兴的未满足的需求，通过：1）通过共- 移植OTC时分离的患者匹配的血管内皮细胞; 2）操作 在卵巢组织移植时移植部位内的信号传导以抑制过早卵泡 动员;和3）通过预处理减轻烷化剂化疗的性腺毒性影响， AMH的卵巢组织在追求这些目标的过程中，该提案将改善数千人的结果。 已经或将要接受OTC的女性，同时也旨在避免未来患者的风险， OTC和自体移植的费用、痛苦和不确定性。