The role of ghrelin in cisplatin-induced infertility

描述（申请人提供）：超过50%接受顺铂化疗的男性癌症患者将患有长期不育症。这是一个重要的问题，因为这些患者中有许多是儿童或年轻男性，他们在癌症中幸存下来，希望以后再生育。然而，目前还没有治疗化疗引起的不孕症的药物。在顺铂诱导的不孕症的发展中的一个关键因素是生殖细胞凋亡，以及促凋亡介质p53和核因子κ B（NF？B）已经牵连到它的发展。Ghrelin是一种新的激素，具有抗凋亡特性，并抑制NF？其他组织中的B。我们的初步研究表明，它减少顺铂诱导的生殖细胞凋亡。然而，生长激素释放肽在这种情况下的作用机制及其对生育能力的影响尚不清楚。本申请的长期目标是：a）开发用于保持暴露于化疗药物的个体的生育力的新策略和B）建立在这种情况下介导生长素释放肽作用的机制。假设：我们假设生长激素释放肽将防止顺铂诱导的不孕症和下调睾丸NF？顺铂诱导的B和p53活化。我们的具体目标是：1）确定ghrelin给药对顺铂诱导的不孕症的影响; 2）确定ghrelin和顺铂对睾丸p53和NF？B活性。设计和方法：在我们的顺铂诱导的性腺损伤的啮齿动物模型中，我们观察到生长激素释放肽阻止顺铂诱导的睾丸细胞凋亡和NF？B激活。我们现在建议测试ghrelin和顺铂对生育力，p53和NF？B活性，通过开发一种新的转基因小鼠系，已被改造为表达荧光素酶和绿色荧光蛋白的启动子，包含NF？B共有结合位点。基于我们成年模型中产生的数据，我们还将建立青春期前不育模型的可行性。意义：生育是超过80%的癌症化疗长期幸存者的主要生活方式问题。Ghrelin对生育、生殖细胞凋亡和NF？这种情况下的B和p53活性对于开发预防或逆转顺铂和其他化疗剂引起的不育的方法将是重要的。这样的追求对于保持暴露于化疗剂、化学品或辐射的男性的长期生育能力具有相关性。公共卫生相关性：在接受化疗治疗癌症的儿童和男子中，相当一部分人的生殖器官受到损害，导致不育。我们目前还没有一种方法来预防或预测谁会在接受化疗后变得不育;然而，我们的初步工作首次表明，一种名为“ghrelin”的新激素可以预防化疗对生殖器官的这种损害。我们在这里提出的实验将确定ghrelin对生育能力的影响，并将引导我们开发预防或治疗不孕症的新方法。

DESCRIPTION (provided by applicant): More than 50% of male cancer patients subjected to cisplatin-based chemotherapy will suffer from long-term infertility. This is a significant concern because many of these patients are children or young men who survive their cancer and would hope to later reproduce. However, medical treatment for chemotherapy-induced infertility is not currently available. A key factor in the development of cisplatin-induced infertility is germ cell apoptosis, and activation of the proapoptotic mediators p53 and Nuclear Factor kappa B (NF?B) has been implicated in its development. Ghrelin, a novel hormone, has anti-apoptotic properties and suppresses NF?B in other tissues. Our preliminary studies indicate that it reduces cisplatin-induced apoptosis in germ cells. However, ghrelin's mechanism(s) of action in this setting and its effect on fertility are unknown. The long-term objectives of this application are: a) to develop new strategies for preserving fertility in individuals exposed to chemotherapeutic drugs and b) to establish the mechanisms mediating ghrelin's effects in this setting. Hypothesis: We hypothesize that ghrelin will prevent cisplatin-induced infertility and downregulate testicular NF?B and p53 activation induced by cisplatin. Our specific aims are: 1) To determine the effect of ghrelin administration on cisplatin-induced infertility and 2) To establish the effects of ghrelin and cisplatin on testicular p53 and NF?B activity. Design and methods: In our rodent model of cisplatin-induced gonadal damage we have observed that ghrelin prevents cisplatin-induced testicular apoptosis and NF?B activation. We are now proposing to test the effects of ghrelin and cisplatin on fertility, p53 and NF?B activity by exploiting a new transgenic mouse line that has been engineered to express luciferase and green fluorescent protein under control of a promoter that contains NF?B consensus binding sites. Based on the data generated in our adult model, we also will establish the feasibility of a prepubertal model of infertility. Significance: Fertility is the major life-style concern in more than 80% of children and men who are long-term survivors of cancer chemotherapy. Establishing the mechanisms and effects of ghrelin on fertility, germ cell apoptosis and NF?B and p53 activity in this setting will be important to develop methods to prevent or reverse the infertility caused by cisplatin and other chemotherapeutic agents. Such a pursuit will have relevance for maintaining long-term fertility in men who are exposed to chemotherapeutic agents, chemicals or radiation. PUBLIC HEALTH RELEVANCE: A significant proportion of children and men receiving chemotherapy for the treatment of cancer suffer damage to their reproductive organs leading to infertility. We currently do not have a way to prevent or predict who will become infertile after receiving chemotherapy; however, our preliminary work shows for the first time that a new hormone called "ghrelin" prevents this damage to the reproductive organs due to chemotherapy. The experiments we propose here will determine the effects of ghrelin on fertility and will lead us to the development of new ways to prevent or treat infertility.