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

项目摘要/摘要 在过去的30年里，癌症患者的五年存活率有所提高。小儿科的存活率 癌症已经达到80%，年轻的癌症幸存者继续过着大致正常的生活，因为他们的生活- 节省治疗费用。尽管癌症疗法的进步提高了存活率，但这些疗法 对健康的长期不利影响。这些疗法最严重的副作用之一就是脱靶效应。 在生殖细胞上。它会导致组成卵巢储备的原始卵泡的丧失，这被定义为所有 卵巢中的卵泡可用于未来的生育和妇女的内分泌支持。这种治疗的结果是 卵巢功能不全，临床表现为内分泌功能障碍和不孕。青春期前 接受癌症治疗的儿童不能启动青春期，需要医疗帮助来维持他们的 正常的生活。因此，制定有效的干预措施是该领域尚未得到满足的需要。有人提议， 某些干预剂具有保护卵巢储备免受癌症治疗影响的效果。然而， 这些辅助疗法的抗生育作用的机制在很大程度上仍然是推测的。 因此，我们的目标是阐明性腺激素治疗如何耗尽原始卵泡的机制。 卵巢储备，开发基于原始卵泡机制的新型胚胎保护剂 消耗，并机械地将辅助性精子保护策略与特定的性腺毒性治疗相匹配。 对原始卵泡丢失的机制提出了几种理论解释。“倦怠”理论 化疗药物通过激活途径激活休眠的原始卵泡。另一个 理论认为，化疗药物通过“凋亡途径”破坏原始卵泡，这是由于 对DNA损伤的敏感性。我们的初步数据表明，在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)阐明其作用机制 6种常见促性腺激素对卵巢储备的耗竭作用，(2)阐明原始细胞的细胞机制 转基因小鼠模型中促性腺激素对卵泡的消耗，以及(3)检测其疗效 以及保护卵巢储备的辅助治疗的安全性。我们建议的研究将产生重大影响 通过(1)阐明特定化疗药物耗尽原始卵泡的机制， 并通过(2)检测候选佐剂对特定抗体的临床前保护效果和安全性 化疗药物。我们的研究可能为精液保护剂的战略选择提供指导 根据对常见促性腺激素的作用机制，对青春期前儿童进行治疗 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.