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Human dopamine transporter gene: variation and transcriptional regulation

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:
10472586
负责人:
Zhicheng Carl Lin
金额:
$41.0万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
未结题
起止时间:
2007-09-01 至 2025-07-31

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中文摘要
翻译
这项更新建议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)。多巴胺转运体(DAT)调节脑组织的时空结构域。 多巴胺通过重新摄取和释放多巴胺进行神经传递,从而有助于运动, 动机、认知和注意力、工作记忆、行为组织和荷尔蒙释放。这很好 认识到DAT基因在大脑中的表达是高度受限的,因人而异 并可受内源性和外源性因素的调节,如物质使用和压力。 DAT表达的改变可能有助于HDAT相关的病理生理状态,如物质使用 精神障碍(肥皂泡)。然而,关于HDAT表达如何调节以及DNA序列如何的信息 变异对调控表达的影响在很大程度上仍然是零星的。这里要检验的假设是 有观点认为,新的转录因子(TF)通过无序调控HDAT启动子。 关联的顺式作用站点。我们的初步研究表明,转录因子可能调节HDAT启动子在一个 互动的方式。因此,这个项目的三个具体目标是:1)展示一种RNA-蛋白质复合体 2)证实了Tf介导的5‘和3’顺式作用位点之间的拮抗作用; 以及3)确定与两个功能VNTRs结合的转录因子以进行启动子调控。结果将从根本上增加 关于HDAT受信号通路调控的铅部位的知识,并赋予相关的风险 大脑紊乱。
英文摘要
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.
期刊论文(31)
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会议论文
Ventral midbrain correlation between genetic variation and expression of the dopamine transporter gene in cocaine-abusing versus non-abusing subjects.
可卡因滥用者与非滥用者的遗传变异与多巴胺转运蛋白基因表达之间的腹中脑相关性。
DOI: 10.1111/j.1369-1600.2011.00391.x
发表时间: 2014
期刊: Addiction biology
影响因子: 3.4
作者: [Zhou,Yanhong, Michelhaugh,SharonK, Schmidt,CarlJ, Liu,JunS, Bannon,MichaelJ, Lin,Zhicheng]
通讯作者: Lin,Zhicheng
DOI: 10.1016/j.pnpbp.2010.11.001
发表时间: 2011-07-01
期刊: Progress in neuro-psychopharmacology & biological psychiatry
影响因子: 5.6
作者: [Xu M, Lin Z]
通讯作者: Lin Z
DOI: 10.2217/pgs.13.141
发表时间: 2013-09
期刊: Pharmacogenomics
影响因子: 2.1
作者: [Zhao Y, Xiong N, Liu Y, Zhou Y, Li N, Qing H, Lin Z]
通讯作者: Lin Z
DOI: 10.1038/s41598-017-17796-y
发表时间: 2017-12-12
期刊: Scientific reports
影响因子: 4.6
作者: [Liu QR, Canseco-Alba A, Zhang HY, Tagliaferro P, Chung M, Dennis E, Sanabria B, Schanz N, Escosteguy-Neto JC, Ishiguro H, Lin Z, Sgro S, Leonard CM, Santos-Junior JG, Gardner EL, Egan JM, Lee JW, Xi ZX, Onaivi ES]
通讯作者: Onaivi ES
17
    Monitoring DAT in Live Rats
    • 批准号:
      8440730
    • 项目类别:
    • 资助金额:
      $18.96万
    • 财政年份:
      2012
    • 负责人:
      Zhicheng Carl Lin
    • 依托单位:
    Monitoring DAT in Live Rat
    • 批准号:
      8322983
    • 项目类别:
    • 资助金额:
      $19.75万
    • 财政年份:
      2012
    • 负责人:
      Zhicheng Carl Lin
    • 依托单位:
    Human Dopamine Transporter Gene: Variation and Transcriptional Regulation
    • 批准号:
      8675815
    • 项目类别:
    • 资助金额:
      $24.89万
    • 财政年份:
      2007
    • 负责人:
      Zhicheng Carl Lin
    • 依托单位:
    Human dopamine transporter gene: variations and transcriptional regulation
    • 批准号:
      7491627
    • 项目类别:
    • 资助金额:
      $31.56万
    • 财政年份:
      2007
    • 负责人:
      Zhicheng Carl Lin
    • 依托单位:
    海外基金