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: 10640051
• 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/10640051
• 关键词: Alcohol consumption; Alcohols; Applications Grants; Biological Models; Biomedical Research; Cell Line; Cell model; Cells; Chromosome 4; Clinical; Clinical Trials; Data; Disease; Ethanol; FDA approved; Functional disorder; Funding; Genes; Genetic; Genetic Markers; Genomics; Goals; Human; Induced pluripotent stem cell derived neurons; K-Series Research Career Programs; Maps; 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; Psychiatry; Regulation; Research; Research Personnel; Research Project Grants; Resources; 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; 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; participant enrollment; 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.

项目总结/文摘