Clinical Genomics and Experimental Therapeutics

临床基因组学和实验治疗学

• 批准号: 9561850
• 负责人: Falk Lohoff
• 金额: $ 259.87万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9561850
• 关键词: Affect; Alcohol consumption; Alcohol dependence; Alcohols; Anxiety Disorders; Area; Autopsy; Biological Markers; Blood; Brain; Cardiovascular system; Clinical; Clinical Protocols; Clinical Research; Complex; DNA; DNA Methylation; DNA sequencing; Data Analyses; Data Set; Development; Disease; Emotions; Environmental Risk Factor; Enzymes; Epigenetic Process; Extinction (Psychology); Fright; Functional Imaging; Functional disorder; Generalized Anxiety Disorder; Genes; Genetic; Genomics; Genotype; Goals; Heavy Drinking; Hepatocyte; Human; Individual; Individual Differences; Intervention; Investigational Therapies; LDL Cholesterol Lipoproteins; Life Stress; Liver; Low-Density Lipoproteins; Methods; Molecular; Neurobiology; Neurons; Pathway interactions; Patients; Pharmacogenetics; Pharmacological Treatment; Pharmacology; Phase; Phenotype; Post-Traumatic Stress Disorders; Proprotein Convertases; Proteomics; Protocols documentation; Public Health; Recruitment Activity; Regulation; Relapse; Research; Risk; Sample Size; Sampling; Side; Subtilisins; Suggestion; Tissues; Translating; Treatment outcome; Variant; Work; addiction; alcohol abuse therapy; alcohol use disorder; body system; clinical imaging; cohort; emotion regulation; epigenetic regulation; epigenome-wide association studies; experimental study; genetic approach; genetic risk factor; genome wide association study; genome-wide; genome-wide analysis; human population genetics; interest; light effects; lipid metabolism; molecular marker; negative affect; neurobiological mechanism; next generation; novel therapeutics; pre-clinical; precision medicine; preclinical study; problem drinker; receptor; success; transcriptome sequencing; treatment response; venlafaxine

Alcohol Use Disorder (AUD) is a common relapsing disorder with significant effects on personal and public health. Various pathways to the development of AUD exist and include both environmental and genetic risk factors that likely interact with each other. Our section is focused on identifying some of those factors. Although there has been limited success in the past in identifying underlying genetic risk factors for AUD, the field of epigenetics in AUD is recently developing (Tawa et al, 2016). New advances are making it feasible to conduct epigenome-wide association studies (EWAS) of complex phenotypes using DNA methylation. A few EWAS for AUD exist, but they are limited by small sample size, low array capture, tissue type, analysis strategy and data interpretation. Currently, no universal DNA methylation loci for AUD have been identified. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome wide methylomic variation in AUD using samples from independent cohorts involving post-mortem brain, blood and liver tissue as well as various clinical and imaging phenotypes with the goal of identifying disease-associated methylomic DNA variation. Results show that the gene encoding the enzyme Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) was the primary target of epigenetic changes relevant to AUD across data sets (Lohoff et al, 2017) . Interestingly, PCSK9 is predominantly expressed in the liver, where it is synthesized and secrete. It primarily targets low-density lipoprotein cholesterol receptors (LDL-R) in the liver cells and interferes with the regulation of LDL cholesterol (LDL-C) in the blood. Epigenetic regulation of PCSK9 expression by alcohol consumption is one potential mechanism explaining lipid metabolism abnormalities found in patients with heavy alcohol use and on the flip-side explaining protective cardiovascular (CV) effects of light to moderate alcohol consumption. Our section also continued to recruit under the clinical protocol 15-AA-0127: (Epi)Genetic Modulators of fear extinction in Alcohol Dependence. This protocol aims to investigate underlying neurobiology and neurocircutiries of fear extinction in individuals with AUD with and without early life stress. Recruitment is ongoing. Related to this project we completed a whole genome association study of treatment response to Venlafaxine XR in generalized anxiety disorder (Jung et al, 2017). We identified several suggestive variants that might predict association with treatment response. In summary, The Section on Clinical Genomics and Experimental Therapeutics (SCGET) 1. Conducts pre-clinical studies and translational clinical studies with focus on genomics and epigenetics related to the pathophysiology and treatment of alcohol use disorders and addictions. 2. Pre-clinical work focuses on identifying molecular mechanisms involved in addictions, utilizing a wide array of methods including human population genetics, genome wide genotyping approaches, next-generation DNA and RNA sequencing, and epigenetic/proteomic profiling. 3. Findings are translated into human clinical studies using molecular biomarker, pharmacogenetic, epigenetic and functional imaging genetic approaches. 4. Clinical studies include early phase 1 / phase 2 proof-of-concept studies of experimental novel therapeutics guided by molecular biomarker profiling.

酒精使用障碍(AUD)是一种常见的复发性障碍，对个人和公共健康有重大影响。AUD的发展存在多种途径，其中包括可能相互作用的环境和遗传风险因素。我们的部分重点是确定其中的一些因素。 尽管过去在确定AUD的潜在遗传风险因素方面取得的成功有限，但AUD的表观遗传学领域最近正在发展(Tawa等人，2016)。新的进展使使用DNA甲基化对复杂表型进行表观基因组范围的关联研究(Ewas)成为可能。目前已有一些用于AUD分析的方法，但其存在样本量小、阵列捕获率低、组织类型、分析策略和数据解释等方面的局限性。目前，还没有发现AUD的通用DNA甲基化位点。 鉴于酒精影响许多器官系统，我们对AUD的全基因组甲基组变异进行了跨组织和交叉表型分析，使用了涉及死后脑、血和肝组织的独立队列样本以及各种临床和成像表型，目的是识别与疾病相关的甲基组DNA变异。结果表明，编码酶原蛋白转换酶枯草杆菌/可信9(PCSK9)的基因是与AUD相关的表观遗传变化的主要目标(Lohoff等人，2017)。有趣的是，PCSK9主要在肝脏表达，在那里它被合成和分泌。它主要针对肝细胞中的低密度脂蛋白胆固醇受体(LDL-R)，并干扰血液中低密度脂蛋白胆固醇(LDL-C)的调节。饮酒对PCSK9表达的表观遗传调节是解释重度饮酒患者脂代谢异常的一种潜在机制，另一方面解释了轻度至中度饮酒对心血管的保护作用。 我们部门还继续根据临床方案15-AA-0127：(EPI)酒精依赖中恐惧消退的遗传调节剂进行招募。该方案旨在研究在有和没有早期生活压力的AUD患者中潜在的神经生物学和恐惧消退的神经回路。招聘工作正在进行中。与该项目相关，我们完成了文拉法辛XR对广泛性焦虑症治疗反应的全基因组关联研究(Jung等人，2017年)。我们确定了几个可能预测与治疗反应相关的提示性变异。 总之，临床基因组学和实验治疗学(SCGET)部分 1.开展以基因组学为重点的临床前研究和转化性临床研究 以及与酒精使用障碍和成瘾的病理生理学和治疗有关的表观遗传学。 2.临床前工作侧重于确定与成瘾有关的分子机制， 利用广泛的方法，包括人类群体遗传学，全基因组 基因分型方法、下一代DNA和RNA测序以及 表观遗传学/蛋白质组学。 3.使用分子生物标记物将发现转化为人类临床研究， 药物遗传学、表观遗传学和功能成像遗传学方法。 4.临床研究包括分子生物标志物图谱指导下的实验性新疗法的早期阶段1/阶段2的概念验证研究。