Leveraging systems pharmacology to advance precision medicine for Gabapentin treatment of AUD

利用系统药理学推进加巴喷丁治疗 AUD 的精准医学

• 批准号: 10887866
• 负责人: Charles R. Marmar
• 金额: $ 16.95万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10887866
• 关键词: Affect; Alcohol consumption; Alcohols; Amino Acid Transporter; Amino Acids; Apoptotic; Biological Markers; Computer Models; Computing Methodologies; DNA; Data; Economic Burden; Epigenetic Process; Funding; Genetic Polymorphism; Genomics; Goals; Individual; Individual Differences; Inflammatory; Life; Marker Discovery; Medical; Mental disorders; Modeling; Molecular; National Institute on Alcohol Abuse and Alcoholism; Oxidative Stress; Participant; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Post-Traumatic Stress Disorders; Property; RNA; Resources; Rewards; Sampling; Serotonergic System; Substance Use Disorder; System; Time; Transcript; alcohol abuse therapy; alcohol use disorder; comorbidity; disability; gabapentin; genomic predictors; individual response; microRNA biomarkers; neurotrophic factor; novel; personalized medicine; precision medicine; preventable death; responders and non-responders; response; social; voltage

Project Summary / Abstract The overall goal of this proposal is to leverage systems pharmacology to advance precision medicine for gabapentin treatment of AUD. The current proposal will utilize DNA and RNA samples available from a completed NIAAA sponsored study on Gabapentin Enacarbil Extended – Release (GE-XR) for AUD and resources from our NYU Center for PrecisionMedicine in Alcohol Use Disorder and PTSD. Our Center was created in September 2018 with funding from an NIAAA P01 “Leveraging biomarkers for personalized treatment of alcohol use disorder comorbid with PTSD”. Our NYU Center focuses on advancing precision medicine for alcohol use disorders, including those comorbid with PTSD, utilizing molecular and circuit markers and advanced computational models for determining responders and non-responders to treatment. The primary aims focused to advance precision medicine by discovering pharmagenomic, pharmacoepigenomic and pharmacotranscriptomic predictors of individual differences in responses to GE-XR treatment of AUD. There will be eight pathways to be prioritized as part of the primary aims of the proposal. The pathways are: voltage sensitive channels, excitatory and inhibitory amino acids, gabapentin amino acid transporters, serotonin pathway, rewarding properties of alcohol, neuor- inflammatory, apoptotic/oxidative stress and neurotrophic factors. The secondary aim focuses on discovering novel targets and pathways. The group will utilize polymorphisms, epigenetic marks, transcripts and miRNA markers for discovery of novel targets and pathways for predicting individual responses in alcohol use in participants. The data to be ascertained from the proposed aims have potential for discovery of novel genomic features to predict responders and non-responders for GE-XR treatment of AUC. These discoveries would significantly contribute to the NIAAA goal of advancing precision medicine within the domain of AUC. More broadly, the novel computational methods that we will advance in this proposal for modelling genomic predictors of likely responders hold promise for advancing precision medicine for other medications for AUD and for personalized treatments of other substance use disorders.

项目摘要/摘要 这项提案的总体目标是利用系统药理学来推动精准医学的发展 加巴喷丁治疗AUD目前的提议将利用从已完成的 NIAAA赞助的AUD用加巴喷丁阿卡比利缓释(GE-XR)研究及来源 我们纽约大学酒精使用障碍和创伤后应激障碍的精准医学中心。我们的中心成立于9月 NIAAA P01《利用生物标记物对酒精使用障碍进行个性化治疗》的资助 与创伤后应激障碍并存“。我们的纽约大学中心专注于推进酒精使用障碍的精准医学， 包括与创伤后应激障碍并存的疾病，利用分子和电路标记以及先进的计算模型 用于确定对治疗有效和无效的患者。主要目标是提高精确度 通过发现药物组学、药物表观组学和药物转录组预测因子 Ge-XR对AUD治疗反应的个体差异。将有八条途径优先考虑 该提案的部分主要目的。这些通路包括：电压敏感通道、兴奋性通道和抑制性通道 氨基酸，加巴喷丁氨基酸转运体，5-羟色胺途径，酒精的奖赏特性，中性- 炎症、凋亡/氧化应激和神经营养因子。第二个目标是发现 新的目标和途径。该小组将利用多态、表观遗传标记、转录本和miRNA 发现新靶点和预测饮酒个体反应途径的标记物 参与者。从提出的目标中确定的数据有可能发现新的基因组 预测GE-XR治疗AUC的应答者和无应答者的功能。这些发现将会 为NIAAA在AUC领域内推进精准医学的目标做出重大贡献。更多 概括地说，我们将在这个提案中提出的建模基因组预测因子的新计算方法 的可能的应答者承诺为澳大利亚和澳大利亚的其他药物推进精准医学 其他物质使用障碍的个性化治疗。

项目成果

Gabapentin Enacarbil Extended-Release Versus Placebo: A Likely Responder Reanalysis of a Randomized Clinical Trial.

• DOI: 10.1111/acer.14414
• 发表时间: 2020-09
• 期刊: Alcoholism, clinical and experimental research
• 作者: Laska EM;Siegel CE;Lin Z;Bogenschutz M;Marmar CR
• 通讯作者: Marmar CR