PQ#12; Targeting Nampt-mediated NAD+ metabolism in chemobrain

项目总结 化疗引起的认知功能障碍(称为化疗障碍)对癌症有负面影响 幸存者，并已成为一个重大的医疗问题。到目前为止，还没有有效的治疗方法，因为 对化疗引起的认知障碍的驱动机制的了解有限。要提供 针对这一紧急医学问题的有效治疗策略，此应用程序旨在回答挑衅性 问题12：癌症发生的分子和细胞机制是什么？ 治疗引发的严重不良后遗症？虽然潜在的分子通路容易受到 化疗引起的神经毒性还不是很清楚，我们实验室最近的结果表明 NAMPT介导的NAD通路是一种很有前途的化疗靶点。使用以铂为基础的 化疗化合物顺铂，我们证明了它对烟酰胺磷酸核糖的抑制作用 转移酶(NAMPT)介导的NAD代谢途径。顺铂对NAMPT-NAD的抑制作用 新陈代谢导致成年小鼠海马神经性功能障碍和记忆障碍。 值得注意的是，我们发现，通过给予NAD前体烟酰胺来增加NAD水平 单核苷酸(NMN)可有效逆转顺铂诱导的神经元树突形态缺陷 和记忆功能，从而强调了NAD代谢在改善老年痴呆方面的治疗潜力 化疗枪。基于这些观察，我们的中心假设是增加NAMPT或NAD水平 预防顺铂引起的神经元和认知功能损伤。我们的发现代表了一种新的 化疗脑损伤的治疗策略。为了检验这一新的假设，目标1将确定是否增加 补充NMN的NAD水平可以改善顺铂诱导的神经元和认知障碍 对幼龄和老年小鼠都有作用。此外，我们的翻译提案将确保NMN的安全，因为我们 将确定NMN是否对患者来源的顺铂的抗肿瘤活性有不利影响 异种移植(PDX)小鼠模型。随后，AIM 2将阐明基因增加的NAMPT水平是否可以 预防神经元形态和认知功能的损伤。我们还将评估P7C3，一个NAMPT 酶活性增强剂，可改善顺铂诱导的幼龄和老年小鼠化疗反应。我们的建议 这项工作将提供关键的病理生理机制，并提高我们对NAMPT介导的 NAD代谢途径，以改善化疗所致认知功能障碍。归根结底， 研究结果将提供一个框架，通过该框架可以对患者使用安全有效的治疗策略。 接受癌症治疗以最小化或逆转神经元和记忆功能障碍。

PROJECT SUMMARY Chemotherapy-induced cognitive dysfunction (referred to as chemobrain) negatively impacts cancer survivors and has emerged as a significant medical problem. To date, no effective treatment exists due to the limited understanding of the mechanisms that drive chemotherapy-induced cognitive impairments. To provide effective therapeutic strategies for this emergent medical problem, this application aims to answer Provocative Question #12: What are the molecular and cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae? While the underlying molecular pathways vulnerable to chemotherapy-induced neurotoxicity are not well understood, recent results from our laboratory indicate the Nampt-mediated NAD+ pathway is a promising therapeutic target for chemobrain. Using the platinum-based chemotherapy compound cisplatin, we demonstrate its efficacy in suppressing the nicotinamide phosphoribosyl transferase (Nampt)-mediated NAD+ metabolic pathway. Cisplatin-mediated suppression of Nampt-NAD+ metabolism leads to neurogenic dysfunction of the adult mouse hippocampus and memory impairments. Remarkably, we found that by increasing NAD+ levels via administration of the NAD+ precursor nicotinamide mononucleotide (NMN), we can effectively reverse cisplatin-induced deficits in neuronal dendrite morphology and memory function, thus emphasizing the therapeutic potential of NAD+ metabolism in amelioration of chemobrain. Based on these observations, our central hypothesis is that increasing Nampt or NAD+ levels prevent cisplatin-induced impairments in neuronal and cognitive function. Our findings represent a novel therapeutic strategy for chemobrain. To test this novel hypothesis, Aim 1 will determine whether increasing NAD+ levels through NMN supplementation can improve cisplatin-induced deficits in neuronal and cognitive function in both young and aged mice. In addition, our translational proposal will ensure the safety of NMN, as we will determine if NMN has a detrimental impact on anti-neoplastic activity of cisplatin using patient-derived xenograft (PDX) mouse models. Subsequently, Aim 2 will elucidate if genetically increasing Nampt levels can prevent impairments in neuronal morphology and cognitive function. We will also evaluate if P7C3, a Nampt enzyme activity enhancer, can improve cisplatin-induced chemobrain in young and aged mice. Our proposed work will provide critical pathophysiological mechanisms and improve our understanding of the Nampt-mediated NAD+ metabolic pathway in order to improve chemotherapy-induced cognitive dysfunction. Ultimately, the findings will provide a framework by which safe and effective therapeutic strategies may be utilized in patients undergoing cancer treatment so as to minimize or reverse neuronal and memory dysfunction.