The Role of miRNAs in Cocaine Addiction

描述（由申请人提供）：了解药物成瘾的分子机制对于开发治疗这种使人衰弱的疾病的新方法至关重要。最近的研究结果表明，小鼠成瘾行为的发展与基因表达的稳定变化有关。成瘾的遗传基础提出了一个问题，即在成瘾中起关键作用的基因及其调节因子的性质。我们发现，小鼠可卡因成瘾的建立与纹状体（负责药物成瘾的大脑区域）中许多miRNA的表达变化有关。鉴于miRNA在基因表达调控中的强大作用，我们假设可卡因调节的miRNA有助于建立支持成瘾的基因表达网络。为了评估可卡因诱导的miRNA对可卡因成瘾的发展和维持的贡献，我们提出解决纹状体特异性改变个体miRNA对成瘾的影响。小鼠中两种最明确的成瘾症状，如可卡因诱导的敏化和奖励，将用于解决miRNA对动物行为的作用。我们将测试长期可卡因治疗影响的miRNA水平的校正是否会影响体内成瘾行为的发展。可卡因处理诱导的miRNA的失活将通过将基于RNA的细胞可渗透的特异性miRNA抑制剂注射到纹状体中来实现。反过来，通过使用表达miRNA的腺相关病毒（AAV），将实现被可卡因抑制的miRNA的纹状体特异性正常化。鉴定在可卡因成瘾的发展和维持中发挥作用的特定miRNA可能有助于揭示控制健康和疾病中多巴胺信号传导的分子网络。此外，通过合成的miRNA拮抗剂靶向成瘾相关的miRNA可能导致开发用于治疗成瘾的新的和高度特异性的方法。 公共卫生相关性：药物成瘾的广泛和社会医学影响决定了有必要开发有效和选择性的药物来治疗这种有害的疾病。在我们的研究中，我们建议探索选择性纠正基因功能的可能性，以达到抗成瘾治疗的目的。我们发现成瘾的发展与miRNAs的异常表达有关，miRNAs是一类新型的高效且具有同等选择性的基因表达调节因子。我们将测试通过可卡因治疗改变的miRNA表达的正常化是否会使大脑功能正常化并治愈成瘾。

DESCRIPTION (provided by applicant): Understanding of the molecular mechanisms of drug addiction is essential for the development of novel approaches for the treatment of this debilitating disease. Recent findings showed that development of addictive behavior in mice is associated with stable changes in gene expression. The genetic basis of addiction raises the question about the nature of genes and their regulators that play a critical role in addiction. We found that establishment of cocaine addiction in mice is associated with expression changes of numerous miRNAs in the striatum, a brain area responsible for drug addiction. Given the potent role of miRNAs in regulation of gene expression, we hypothesize that cocaine regulated miRNAs contribute to the establishment of the gene expression network that supports addiction. To evaluate the contribution of cocaine induced miRNAs to the development and maintenance of cocaine addiction we propose to address the impact of striatum specific alteration of individual miRNAs on addiction. The two most well defined symptoms of addiction in mice such as cocaine induced sensitization and reward will be used to address the role of miRNA on animal behavior. We will test whether correction of miRNA levels affected by chronic cocaine treatment affects the development of addictive behavior in vivo. Inactivation of miRNA that are induced by cocaine treatment will be achieved by injection of the RNA based cell-permeable specific miRNA inhibitors into the striatum. In turn, striatum specific normalization of miRNA that are suppressed by cocaine will be achieved by using miRNA expressing adenoassociated virus (AAV). Identification of specific miRNAs that play a role in the development and maintenance of cocaine addiction may help to reveal molecular networks controlling dopamine signaling in health and disease. Furthermore, targeting of the addiction-associated miRNAs by synthetic miRNA antagonists may lead to development of novel and highly specific approach for treatment of addiction. PUBLIC HEALTH RELEVANCE: The widespread and sociomedical impact of drug addiction dictates the necessity to develop efficient and selective drugs for the treatment of this harmful disease. In our studies we propose to explore the possibility of selective correction of gene function for the purpose of anti-addictive therapy. We found that the development of addiction is associated with aberrant expression of miRNAs, a novel class of highly potent and equally selective regulators of gene expression. We will test whether normalization of the miRNA expression, altered by cocaine treatment, will normalize brain function and cure addiction.