Salivary MicroRNAs as Biomarkers for Alcohol Dependence

唾液 MicroRNA 作为酒精依赖的生物标志物

• 批准号: 9059548
• 负责人: Huiping Zhang
• 金额: $ 10.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9059548
• 关键词: Adult; Affect; African American; Age; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; American; Animal Model; Attitude; Autopsy; Biochemical Markers; Biological Markers; Body Fluids; Brain; Cell Culture Techniques; Clinical; Complex; Control Groups; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Economics; European; Extracellular Space; Female; Gene Expression; Gene Targeting; Genetic Variation; Genotype; Goals; Health; Hereditary Disease; Human; Lasso; Logistic Regressions; Methods; MicroRNAs; Modeling; Molecular; Monitor; Patients; Pattern; Performance; Physical Dependence; Play; Prevention; Procedures; Prognostic Marker; Public Health; Questionnaires; Race; Rattus; Receiver Operating Characteristics; Recruitment Activity; Research; Role; Saliva; Salivary; Sampling; Sensitivity and Specificity; Serum; Single Nucleotide Polymorphism; Smoking History; Substance Addiction; Substance Use Disorder; Synapses; Technology; Testing; Tissue Sample; Tissues; Universities; Untranslated RNA; Urine; Work; alcohol exposure; brain tissue; case control; chronic alcohol ingestion; cost; diagnostic biomarker; differential expression; disease diagnosis; drinking; extracellular; genome wide association study; improved; innovation; male; meetings; neuroadaptation; next generation sequencing; novel diagnostics; outcome forecast; potential biomarker; saliva diagnostic; screening; sex; specific biomarkers; therapeutic target; tool; transcriptome; willingness

DESCRIPTION (provided by applicant): Alcohol dependence (AD) is a serious public health concern characterized by alcohol tolerance, physical dependence, and an inability to control one's alcohol intake. It affects approximately 3.8% of adult Americans each year, and causes substantial economic loss annually. Identification of effective biomarkers for AD is critical for A prevention and treatment. Studies of both cell culture and animal models have demonstrated that small non-coding microRNAs (miRNAs), which regulate the expression of their target genes at the post- transcriptional level, are implicated in chronic alcohol consumption-induced neuroadaptations. Emerging evidence supports the presence of miRNAs in extracellular spaces or body fluids (i.e., saliva, serum, urine, etc), suggesting that the extracellular miRNAs are potential biomarkers for disease diagnosis and prognosis. To date, there is very limited information on miRNA expression changes in human AD subjects, and no study is known to have examined miRNA expression alterations in the saliva of AD subjects. The objective of this application is to identify AD-associated salivary miRNAs and explore the possibility of using these salivary miRNAs (in combination with AD-associated SNPs) to predict AD. The central hypothesis is that chronic alcohol consumption induces altered miRNA expression in various tissues, and that these altered expression levels are reflected in the secretion of miRNAs into body fluids such as saliva. This hypothesis will be tested by pursuing three specific aims: (1) profile salivary miRNA transcriptome changes in AD subjects using next- generation sequencing (NGS) in both African Americans and European Americans; and (2) assess the ability of the differentially expressed miRNAs in predicting the status of AD; and (3) combine AD-associated salivary miRNA and AD-associated SNPs (identified in our recent genome-wide association studies) to improve the prediction of AD. We expect to discover a set of AD-associated salivary miRNAs and SNPs that can serve as AD biomarkers. The approach is innovative because miRNA transcriptome alterations in the saliva of AD subjects will be examined by NGS technology, which offers unprecedented sensitivity and specificity in the detection of gene expression. Moreover, integrating miRNA expression and SNP genotype data is expected to greatly improve the prediction of AD. Our long-term goal is to use the identified AD-associated salivary miRNAs as novel diagnostic and prognostic biomarkers and as potential therapeutic targets for AD and AD- related disorders. The proposed research is significant because the identified salivary miRNAs are expected to have clinical implications in monitoring the development of AD. Additionally, the research strategies developed in this proposed study can be applied to identify extracellular miRNAs that are important for other substance use disorders.

描述（由申请人提供）：酒精依赖（AD）是一个严重的公共健康问题，其特征是酒精容忍，身体依赖和无法控制自己的酒精摄入量。它每年影响约3.8％的成年美国人，每年造成大量经济损失。识别有效的AD生物标志物对于预防和治疗至关重要。对细胞培养和动物模型的研究表明，调节其在转录后水平的靶基因表达的小型非编码microRNA（miRNA）与慢性酒精消耗诱导的神经加热有关。新兴证据支持细胞外空间或体液（即唾液，血清，尿液等）中的miRNA，这表明细胞外miRNA是疾病诊断和预后的潜在生物标志物。迄今为止，关于人类AD受试者中miRNA表达变化的信息非常有限，并且尚无研究检查AD受试者唾液中的miRNA表达改变。该应用的目的是识别与AD相关的唾液miRNA，并探索使用这些唾液miRNA（与AD相关的SNP结合使用）来预测AD的可能性。中心假设是，慢性酒精消耗会诱导各种组织中的miRNA表达改变，并且这些改变的表达水平反映在miRNA中的分泌到体液中，例如唾液。该假设将通过追求三个具体目的来检验：（1）使用下一代测序（NGS）在非裔美国人和欧洲美国人中使用下一代测序（NGS）的唾液miRNA转录组变化； （2）评估差异表达的miRNA预测AD状态的能力； （3）结合了与AD相关的唾液miRNA和与AD相关的SNP（在我们最近的全基因组关联研究中鉴定），以改善AD的预测。我们希望发现一套可以用作广告生物标志物的广告相关的唾液miRNA和SNP。该方法具有创新性，因为NGS技术将检查AD受试者唾液中的miRNA转录组改变，该技术在检测基因表达时具有前所未有的灵敏度和特异性。此外，预期整合miRNA表达和SNP基因型数据将大大改善AD的预测。我们的长期目标是将确定的AD相关唾液miRNA用作新颖的诊断和预后生物标志物，并将其作为AD和AD相关疾病的潜在治疗靶标。拟议的研究很重要，因为所鉴定的唾液miRNA有望在监测AD的发展方面具有临床意义。此外，这项拟议的研究中制定的研究策略可用于识别对其他物质使用障碍很重要的细胞外miRNA。