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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要该提案的总体目标是利用系统药理学推进精准医学加巴喷丁治疗 AUD 目前的提案将利用已完成的 DNA 和 RNA 样本。 NIAAA 赞助了针对 AUD 的加巴喷丁 Enacarbil 延长释放 (GE-XR) 的研究以及来自以下机构的资源我们的纽约大学酒精使用障碍和创伤后应激障碍精准医学中心于 9 月成立。 2018 年，由 NIAAA P01“利用生物标记物进行酒精使用障碍的个性化治疗”资助与 PTSD 共病”。我们的纽约大学中心致力于推进针对酒精使用障碍的精准医学，包括那些与 PTSD 共存的患者，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反应和无反应的主要目标是提高精确度。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来进行医学研究 GE-XR 治疗 AUD 的反应存在个体差异，有八种途径需要优先考虑。该提案的部分主要目标是：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、血清素途径、酒精的奖励特性、神经- 炎症、细胞凋亡/氧化应激和神经营养因子是第二个目标。该小组将利用多态性、表观遗传标记、转录本和 miRNA。发现新靶点的标记物和预测个体饮酒反应的途径从提议的目标中确定的数据有可能发现新的基因组。这些发现将对 GE-XR 治疗的 AUC 做出反应的预测者和非反应者的特征。为 NIAAA 在 AUC 领域推进精准医学的目标做出了重大贡献。广泛地说，我们将在本提案中提出用于建模基因组预测因子的新颖计算方法的可能响应者承诺推进 AUD 和其他药物的精准医学其他物质使用障碍的个性化治疗。