Human dopamine transporter gene: variation and transcriptional regulation

人类多巴胺转运蛋白基因：变异和转录调控

• 批准号: 10226304
• 负责人: Zhicheng Carl Lin
• 金额: $ 41万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226304
• 关键词: Affect; Alcohol consumption; Alleles; Attention; Attention deficit hyperactivity disorder; Autopsy; Behavioral; Binding; Bipolar Disorder; Brain; Brain Diseases; Cells; Cocaine; Cognition; Complementary DNA; Complex; Consensus; Cultured Cells; DNA Sequence; Development; Disease; Dopamine; Dose; Endogenous Factors; Enhancers; Eukaryotic Initiation Factors; Exogenous Factors; Exons; Gene Expression; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Transcription; Genetic study; Goals; Haplotypes; Hormones; Human; In Vitro; Individual; Introns; Knowledge; Lead; Locomotion; Mediating; Mental Depression; Midbrain structure; Minisatellite Repeats; Molecular; Molecular Genetics; Motivation; Mus; National Institute of Drug Abuse; Nuclear; Nucleotides; Parkinson Disease; Pathogenicity; Patients; Plasmids; Play; Post-Traumatic Stress Disorders; Precision therapeutics; Proteins; RNA; Regulation; Research; Risk; Risk Factors; Role; Schizophrenia; Short-Term Memory; Side; Signal Pathway; Site; Source; Stress; Substance Use Disorder; Testing; Time; Transcription Initiation Site; Transcriptional Regulation; Untranslated Regions; Validation; Variant; base; cis acting element; cocaine self-administration; cocaine use; dopamine transporter; experimental study; hybrid gene; in vivo; knockout gene; neuropsychiatric disorder; neurotransmission; novel; prevent; programs; promoter; protective factors; protein complex; reuptake; spatiotemporal; substance use; transcription factor; transmission process

The overall goal of this renewal proposal is to dissect genetic transcription mechanisms in the human dopamine transporter gene (hDAT). The dopamine transporter (DAT) regulates the spatio-temporal domains of dopamine neurotransmission by reuptake and release of dopamine and thus contributes to locomotion, motivation, cognition and attention, working memory, behavioral organization and hormone release. It is well recognized that expression of the DAT gene in the brain is highly circumscribed, varies among individual subjects and can be regulated by endogenous and exogenous factors such as substance uses and stress. Altered DAT expression may contribute to hDAT-associated pathophysiological states such as substance use disorders (SUDs). However, information about how hDAT expression is regulated and how DNA sequence variation influences the regulated expression remains largely sporadic. The hypothesis to be tested in this proposal is that novel transcription factors (TFs) play a major role in regulating the hDAT promoter via disorder- associated cis-acting sites. Our preliminary studies show that TFs may regulate the hDAT promoter in an interactive manner. Therefore, three specific aims of this project are to: 1) demonstrate a RNA-protein complex involved in the promoter regulation; 2) confirm a TF-mediated antagonism between 5’ and 3’ cis-acting sites; and 3) identify TFs that bind to two functional VNTRs for promoter regulation. The results will add fundamental knowledge on lead sites through which hDAT is regulated by signaling pathways and confers risks for related brain disorders.

该更新提案的总体目标是剖析人类的基因转录机制 多巴胺转运蛋白基因（hDAT）。多巴胺转运蛋白（DAT）调节时空域 通过多巴胺的再摄取和释放来进行多巴胺神经传递，从而有助于运动， 动机、认知和注意力、工作记忆、行为组织和激素释放。很好 认识到 DAT 基因在大脑中的表达是高度受限的，并且因个体而异 受试者可以通过内源性和外源性因素（例如物质使用和压力）进行调节。 DAT 表达的改变可能导致 hDAT 相关的病理生理状态，例如物质使用 疾病（SUD）。然而，有关 hDAT 表达如何调节以及 DNA 序列如何调节的信息 影响调节表达的变异在很大程度上仍然是零星的。本次要检验的假设 提议认为，新型转录因子 (TF) 在通过紊乱调节 hDAT 启动子方面发挥着重要作用。 相关的顺式作用位点。我们的初步研究表明，TFs 可能以一种方式调节 hDAT 启动子。 互动方式。因此，该项目的三个具体目标是：1）展示RNA-蛋白质复合物 参与发起人监管； 2) 确认 5' 和 3' 顺式作用位点之间存在 TF 介导的拮抗作用； 3) 鉴定与两个功能性 VNTR 结合以进行启动子调控的 TF。结果将增加基本面 关于 hDAT 通过信号通路进行调节并赋予相关风险的先导位点的知识 脑部疾病。