Acamprosate pharmacogenomics: iPSC based model of alcohol use disorder

阿坎酸药物基因组学：基于 iPSC 的酒精使用障碍模型

• 批准号: 10310405
• 负责人: Ming-Fen Ho
• 金额: $ 12.98万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310405
• 关键词: Alcohol consumption; Alcohols; Applications Grants; Biological Models; Biomedical Research; Cell Line; Cell model; Cells; Chromosome 4; Clinical; Clinical Trials; Data; Disease; Enrollment; Ethanol; FDA approved; Functional disorder; Funding; Genes; Genetic; Genetic Markers; Genomics; Goals; Human; K-Series Research Career Programs; Mental disorders; Mentored Research Scientist Development Award; Mentors; Molecular; Molecular Probes; Molecular Profiling; Multiomic Data; National Institute on Alcohol Abuse and Alcoholism; Nature; Neuroglia; Neurons; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Pharmacotherapy; Plasma; Play; Psychiatry; Regulation; Research; Research Personnel; Research Project Grants; Resources; Role; Sampling; Selective Serotonin Reuptake Inhibitor; Series; Serotonin; Therapeutic Agents; Training; Treatment outcome; United States; United States National Institutes of Health; Variant; acamprosate; alcohol abuse therapy; alcohol exposure; alcohol response; alcohol use disorder; base; biobank; cell type; design; drug action; experience; exposed human population; functional genomics; genome wide association study; genome-wide; genomic signature; individual variation; individualized medicine; induced pluripotent stem cell; induced pluripotent stem cell technology; innovation; insight; metabolomics; multiple omics; non-alcoholic; novel; profiles in patients; response; stem cell model; stem cells; therapy outcome; transcriptomics; treatment response

Project Summary/Abstract This application for an NIAAA K01 Career Development Award proposes studies of the pharmacogenomics of alcohol use disorder (AUD) and acamprosate treatment response. Our proposed use of AUD patient-derived induced pluripotent stem cell (iPSC)--an innovative and comprehensive “cell line based” model system will make it possible to advancing our understanding of both drug action and of disease pathophysiology. These results might provide novel mechanistic insight into molecular and genomic signatures for AUD as well as mechanisms underlying individual variation in response to acamprosate. Therefore, the proposed studies include the following aims, Aim 1: To generate a panel of iPSCs from patient-derived LCLs as a novel cell model system for functional genomic studies of AUD and its drug therapy. Aim 2: To identify molecular signatures for alcohol or acamprosate exposure using human neural cells to perform genome-wide transcriptomic profiles using patient-derived iPSC-derived neuronal and glial cell types differentiated from iPSCs obtained from AUD patients and healthy controls. Aim 3: To determine molecular signatures for alcohol and acamprosate exposure, and mechanisms underlying individual variation in those signatures by mapping targeted metabolomic profiles of patient-derived iPSC. The significance of the proposed studies results from the societal importance of AUD and of patient derived iPSC-based research, from the possibility of more highly individualized treatment for AUD, and from the fact that these studies may suggest novel genetic mechanisms that might influence individual variation in acamprosate response in AUD patients. As a result, the proposed studies would have both translational and basic implications for genetic mechanisms that might influence alcohol and acamprosate effect genome-wide and for more highly individualized acamprosate therapy of AUD. In summary, Dr. Ho, the applicant, proposes to take advantage of the NIAAA K01 Award mechanism to broaden her experience with the utilization of multi-omics data (under the direction of her Primary Mentor: Dr. Richard Weinshilboum), translational pharmacogenomics with a focus on AUD (under the guidance of co- mentor: Dr. Victor Karpyak), and iPSC technology (under the guidance of co-mentor: Dr. Zhexing Wen). The resources and mentoring provided by an NIAAA K01 Award would help make it possible for Dr. Ho to achieve her goal of becoming an independent investigator studying molecular and genomic mechanisms of response to alcohol exposure using patient-derived iPSCs and pharmacogenomic studies of acamprosate response in patients with AUD. Receipt of an NIAAA K01 Award would represent a critical step toward Dr. Ho’s ultimate goal of becoming an independent investigator, for obtaining the additional training required to significantly expand the nature of the biomedical research contributions that she might ultimately make and to generate preliminary data in support of an NIH R01 research grant application.

项目摘要/摘要 这份NIAAA K01职业发展奖的申请书提出了对药物基因组学的研究 酒精使用障碍(AUD)和氨基己酸酯治疗反应。我们建议使用AUD患者派生的 诱导多能干细胞(IPSC)--一种创新的、全面的基于细胞系的模型系统将 使我们对药物作用和疾病病理生理学的理解成为可能。这些 这些结果可能为AUD的分子和基因组签名以及 个体变异对氨基己酸酯反应的潜在机制。因此，拟议的研究 包括以下目标，目标1：从患者来源LCL中产生一组IPSCs作为一种新的细胞 AUD及其药物治疗的功能基因组研究模式系统。目标2：鉴定分子 使用人类神经细胞进行全基因组检测的酒精或氨基己酸酯暴露的特征 患者来源的IPSC来源的神经元和神经胶质细胞类型的转录图谱 取自AUD患者和健康对照组的IPSCs。目标3：确定酒精的分子特征 和氨基甲酸酯的暴露，以及通过映射这些特征中的个体差异的机制 患者来源的ipsc的靶向代谢组谱。建议的研究结果的意义来自 AUD和基于患者的IPSC研究的社会重要性，来自更高水平的可能性 AUD的个体化治疗，以及这些研究可能提出新的遗传机制这一事实 这可能会影响AUD患者的氨基己酸酯反应的个体差异。因此，拟议的 研究将对可能的遗传机制具有翻译和基本意义 在全基因组范围内影响酒精和氨基己酸酯的效应，并使其更加个性化 AUD的针刺疗法。 综上所述，申请者何博士建议利用NIAAA K01奖励机制 拓宽她利用多组学数据的经验(在她的主要导师的指导下：Dr。 Richard Weinshilboum)，翻译药物基因组学，重点放在AUD(在联合 导师：Victor Karpyak博士)，和iPSC技术(联合导师：温哲星博士指导)。这个 由NIAAA K01奖提供的资源和指导将有助于何博士实现 她的目标是成为一名研究分子和基因组反应机制的独立研究员 酒精暴露患者来源的IPSCs和阿卡米松反应的药物基因组学研究 AUD患者。获得NIAAA K01奖将代表着朝着何博士的终极目标迈出的关键一步 成为一名独立调查员的目标，以获得必要的额外培训 扩大她最终可能做出和产生的生物医学研究贡献的性质 支持NIH R01研究拨款申请的初步数据。