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: 10629306
• 负责人: Charles R. Marmar
• 金额: $ 75.08万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629306
• 关键词: Affect; Alcohol consumption; Alcohols; Algorithms; Amino Acid Transporter; Amino Acids; Apoptotic; Biological Markers; Brain-Derived Neurotrophic Factor; CASP3 gene; CNR1 gene; CNR2 gene; Calcium; Clinical; Computer Models; Computing Methodologies; DNA; Data; Economic Burden; Enzymes; Epigenetic Process; Funding; GPR55 receptor; Genes; Genetic Polymorphism; Genomics; Genotype; Glial Fibrillary Acidic Protein; Glutamate Transporter; Glutamates; Goals; IL6 gene; Individual; Individual Differences; Inflammatory; Interleukin-1 beta; Life; Marker Discovery; Medical; Mental disorders; MicroRNAs; Mitochondria; Modeling; Molecular; National Institute on Alcohol Abuse and Alcoholism; Neuropharmacology; Opioid; Oxidative Stress; Participant; Pathway interactions; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Placebos; Post-Traumatic Stress Disorders; Property; RNA; Resources; Rewards; Sampling; Serotonergic System; Substance Use Disorder; System; TNF gene; Time; Transcript; Tyrosine 3-Monooxygenase; alcohol abuse therapy; alcohol use disorder; comorbidity; cytochrome c; disability; gabapentin; gamma-Aminobutyric Acid; genome sequencing; genomic predictors; glial cell-line derived neurotrophic factor; individual response; microRNA biomarkers; neuroinflammation; neurotrophic factor; novel; personalized medicine; precision medicine; predictive modeling; preventable death; random forest; receptor; responders and non-responders; response; serotonin 5 receptor; social; transcriptome sequencing; voltage; voltage gated channel; whole genome

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.

项目总结/摘要 该提案的总体目标是利用系统药理学来推进精准医学， 加巴喷丁治疗AUD。目前的建议将利用DNA和RNA样本，从一个完整的 NIAAA赞助的关于加巴喷丁Enacarbil缓释（GE-XR）的AUD研究和来自 我们的纽约大学酒精使用障碍和创伤后应激障碍精密医学中心。我们的中心成立于9月 2018年，由NIAAA P01“利用生物标志物进行酒精使用障碍的个性化治疗”资助 患有创伤后应激障碍“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， 包括那些患有创伤后应激障碍的人，利用分子和电路标记以及先进的计算模型， 用于确定对治疗的应答者和非应答者。主要目标是提高精度 通过发现药物基因组学、药物表观基因组学和药物转录组学预测因子， GE-XR治疗AUD的个体差异。将有八条途径被优先考虑， 这是提案的主要目的之一。这些通路是：电压敏感通道，兴奋性和抑制性 氨基酸，加巴喷丁氨基酸转运蛋白，5-羟色胺途径，酒精的奖赏特性，神经- 炎症、细胞凋亡/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。该小组将利用多态性，表观遗传标记，转录本和miRNA 用于发现新靶点和预测个体对酒精使用反应的途径的标记物， 参与者从所提出的目标中确定的数据具有发现新的基因组的潜力。 预测GE-XR治疗AUC的应答者和非应答者的特征。这些发现将 显著有助于NIAAA在AUC领域内推进精准医疗的目标。更 概括地说，我们将在这个提议中提出的新的计算方法，用于模拟基因组预测因子， 的可能应答者有望推进AUD和其他药物的精确药物治疗， 其他物质使用障碍的个性化治疗。