Acamprosate pharmacogenomics: iPSC based model of alcohol use disorder

项目总结/摘要 NIAAA K 01职业发展奖的申请提出了以下药物基因组学研究： 酒精使用障碍（AUD）和阿坎酸治疗反应。我们建议使用AUD患者源性 诱导多能干细胞（iPSC）--一种创新和全面的“基于细胞系”的模型系统， 使我们对药物作用和疾病病理生理学的理解更进一步成为可能。这些 这些结果可能为AUD的分子和基因组特征提供新的机制见解， 对阿坎酸反应的个体差异的潜在机制。因此，建议的研究 目的1：从患者来源的LCL产生一组iPSC作为新的细胞， 用于AUD及其药物治疗的功能基因组研究的模型系统。目的2：鉴定分子 使用人类神经细胞进行全基因组的酒精或阿坎酸暴露的特征 使用患者来源的iPSC来源的神经元和神经胶质细胞类型的转录组学谱，所述细胞类型分化自 从AUD患者和健康对照获得的iPSC。目的3：确定酒精的分子特征 和阿坎酸暴露，以及通过映射这些签名中个体差异的机制 患者来源的iPSC的靶向代谢组学特征。拟议研究结果的重要性来自 AUD和基于患者的iPSC研究的社会重要性，从更高的可能性， AUD的个体化治疗，以及这些研究可能提示新的遗传机制的事实 可能影响AUD患者中阿坎酸反应的个体差异。因此，拟议的 这些研究将对遗传机制产生转化和基本影响， 影响酒精和阿坎酸影响全基因组和更高度个性化 阿坎酸治疗AUD。 总括而言，申请人何博士建议利用NIAAA K 01奖励机制， 扩大她的经验，利用多组学数据（在她的主要导师的指导下：博士。 Richard Weinshilboum），转译药物基因组学，重点是AUD（在共同指导下， 导师：维克托Karpyak博士）和iPSC技术（在共同导师：温哲兴博士的指导下）。的 NIAAA K 01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独立的研究人员，研究对以下疾病的反应的分子和基因组机制： 使用患者来源的iPSC的酒精暴露和阿坎酸反应的药物基因组学研究 患者AUD获得NIAAA K 01奖将代表何博士向其最终目标迈出关键一步。 目标是成为一名独立的调查员，以获得显著提高 扩大她最终可能做出的生物医学研究贡献的性质， 支持NIH R 01研究资助申请的初步数据。

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.