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

质子Q

基本信息

批准号：
10459278
负责人：
Mi-Hyeon Jang
金额：
$ 38.63万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-08 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459278
关键词：
Adult Affect Anabolism Antineoplastic Agents Behavioral Brain Brain region Cancer Survivor Cell division Cell physiology Cisplatin Clinical Trials Coenzymes Cognitive Cognitive deficits Confocal Microscopy DNA Repair Data Dendrites Dendritic Spines Development Enhancers Ensure Enzymes Functional disorder Gliosis Glycolysis Goals Hippocampus (Brain)Impaired cognition Impairment Laboratories Learning Malignant Neoplasms Malignant neoplasm of ovary Mediating Medical Memory Memory impairment Metabolic Metabolic Pathway Metabolism Molecular Morphology Mus Neuronal Dysfunction Neurons Niacinamide Nicotinamide Mononucleotide Nicotinamide adenine dinucleotide Pathway interactions Patients Pharmaceutical Preparations Pharmacology Platinum Play Process Quality of life Role Safety Supplementation Testing Therapeutic Transferase Translational Research United States Work age related neurodegeneration aged base behavior test cancer therapy chemobrain chemotherapy clinically relevant cognitive function cohort comorbidity drug development effective therapy enzyme activity healthspan improved insight mouse genetics mouse model myelination neurogenesis neurotoxicity novel novel therapeutic intervention older patient overexpression patient derived xenograft model prevent side effect stem therapeutic target therapeutically effective

项目摘要

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.

项目概要化疗引起的认知功能障碍（称为化疗脑）对癌症产生负面影响幸存者并已成为一个重大的医疗问题。迄今为止，尚无有效的治疗方法，因为对化疗引起的认知障碍的机制了解有限。提供针对这一紧急医疗问题的有效治疗策略，该应用程序旨在回答挑衅性的问题问题#12：癌症发生的分子和细胞机制是什么治疗引起的严重不良后遗症？虽然潜在的分子途径容易受到化疗引起的神经毒性尚不清楚，我们实验室的最新结果表明 Nampt 介导的 NAD+ 通路是化学脑的一个有前途的治疗靶点。使用铂基化疗化合物顺铂，我们证明了其抑制烟酰胺磷酸核糖的功效转移酶 (Nampt) 介导的 NAD+ 代谢途径。顺铂介导的 Nampt-NAD+ 抑制代谢导致成年小鼠海马神经源性功能障碍和记忆障碍。值得注意的是，我们发现通过施用 NAD+ 前体烟酰胺来增加 NAD+ 水平单核苷酸（NMN），我们可以有效逆转顺铂引起的神经元树突形态缺陷和记忆功能，从而强调了 NAD+ 代谢在改善化学脑。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。我们的发现代表了小说化疗脑的治疗策略。为了检验这个新假设，目标 1 将确定是否增加通过补充 NMN 提高 NAD+ 水平可以改善顺铂引起的神经元和认知缺陷在年轻和老年小鼠中均发挥作用。此外，我们的翻译提案将确保 NMN 的安全，因为我们将使用患者来源的药物来确定 NMN 是否对顺铂的抗肿瘤活性有不利影响异种移植（PDX）小鼠模型。随后，目标 2 将阐明基因增加 Nampt 水平是否可以防止神经元形态和认知功能受损。我们还将评估 P7C3（Nampt）是否酶活性增强剂，可以改善顺铂诱导的年轻和老年小鼠的化学脑。我们提出的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引起的认知功能障碍。最终，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，以尽量减少或逆转神经元和记忆功能障碍。