Development of mechanism-based ovarian reserve protecting adjuvant therapies against gonadotoxic therapeutic agents

项目概要/摘要 癌症患者的五年生存率在过去三十年中有所提高。儿童的存活率 癌症已经达到80%，年轻的癌症幸存者继续过着正常的生活，因为他们的生活- 拯救治疗虽然癌症治疗的进步提高了生存率，但这些治疗方法 对健康的长期不良影响。这些疗法最严重的副作用之一是脱靶效应 在生殖细胞上。它导致包括卵巢储备在内的原始卵泡的损失，这被定义为所有 卵巢中的卵泡可用于未来的生育和女性内分泌支持。该处理导致 卵巢功能不全，临床表现为内分泌功能紊乱和不孕。青春前期 接受癌症治疗的孩子不能开始青春期，需要医疗帮助来维持他们的青春期。 正常的生活因此，制定有效的干预措施是该领域尚未满足的需求。已经提出 某些干预剂具有保护卵巢储备免受癌症治疗的功效。但 这些辅助疗法的胎儿保护作用的潜在机制仍然主要是推测性的。 因此，我们的目标是阐明性腺毒性治疗如何消耗原始卵泡的机制， 卵巢储备功能，开发基于原始卵泡机制的新型生育保护剂 消耗，并机械匹配辅助fertoprotective策略与特定的性腺毒性治疗。 已经提出了几种理论来解释原始卵泡丢失的机制。“燃烧”理论 化疗剂通过激活途径激活休眠的原始卵泡。另一 理论是化疗剂通过“凋亡途径”破坏原始卵泡， 对DNA损伤的敏感性我们的初步数据表明卵母细胞中存在两种不同的凋亡途径 原始卵泡因DNA损伤而死亡。在强有力的初步数据支持的指导下，我们建议测试 6种常见的化疗药物和基于信号通路的抑制剂（1），以阐明 6种常用的促性腺激素对卵巢储备功能的影响;（2）阐明卵巢储备功能低下的细胞机制 在遗传修饰的小鼠模型中通过性腺毒性剂去除卵泡，以及（3）检查功效 和卵巢储备保护辅助治疗的安全性。我们提出的研究将产生重大影响 在该领域通过（1）阐明特异性化疗剂消耗原始卵泡的机制， 和通过（2）测试候选佐剂对特异性抗体的临床前胎儿保护功效和安全性， 化疗剂。我们的研究可能为生育保护剂的战略选择提供指导 基于对将接受治疗的青春期前儿童的常见性腺毒性剂的作用机制， 癌症治疗。

PROJECT SUMMARY/ABSTRACT The five-year survival rate of cancer patients has improved in the last thirty years. The survival rate of pediatric cancers has reached 80%, and the young cancer survivors go on to live generally normal lives due to their life- saving treatments. Although advances in cancer therapies increased the survival rate, these therapies have long-term adverse health effects. One of the most serious side effects of those therapies is the off-target effect on germ cells. It causes the loss of primordial follicles that consist of ovarian reserve, which is defined as all of the follicles in the ovary available for future fertility and endocrine support for women. This treatment results in premature ovarian insufficiency, which clinically presents as endocrine dysfunction and infertility. Prepubertal kids who are treated with cancer therapies cannot initiate puberty and need medical help for maintaining their normal life. Thus, developing an effective intervention is an unmet need in the field. It has been proposed that certain intervention agents have the efficacy to protect ovarian reserves from cancer therapies. However, the mechanisms underlying the fertoprotective effects of these adjuvant therapies remain largely speculative. Therefore, our goals are to clarify the mechanisms on how gonadotoxic therapies deplete primordial follicles in the ovarian reserve, develop novel fertoprotective agents based on the mechanisms of primordial follicle depletion, and mechanistically match adjuvant fertoprotective strategies with specific gonadotoxic treatments. Several theories have been proposed to explain the mechanism of primordial follicle loss. The "burn out" theory is that chemotherapeutic agents activate dormant primordial follicles through an activation pathway. Another theory is that chemotherapeutic agents destroy primordial follicles through an “apoptotic pathway” due to high sensitivity to DNA damage. Our preliminary data suggest that there are two distinct apoptotic pathways in oocyte death in primordial follicles by DNA damages. Guided by strongly supported preliminary data, we propose to test 6 common chemotherapeutic agents and signaling pathway-based inhibitors (1) to elucidate the mechanisms of ovarian reserve depletion by 6 common gonadotoxic agents, (2) to elucidate the cellular mechanism of primordial follicle depletion by gonadotoxic agents in genetically modified mouse models, and (3) to examine the efficacy and safety of ovarian reserve-protecting adjuvant therapies. Our proposed studies will have a significant impact on the field by (1) clarifying mechanisms by which specific chemotherapeutic agents deplete primordial follicles, and by (2) testing the preclinical fertoprotective efficacy and safety of candidate adjuvants against specific chemotherapeutic agents. Our studies may inform guidelines for strategic selection of fertoprotective agents based on the mechanism of action against common gonadotoxic agents to prepubertal kids who will be treated with cancer therapies.