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.

项目摘要/摘要