Cocaine Regulation of FosB Splicing

可卡因对 FosB 剪接的调节

基本信息

项目摘要

DESCRIPTION (provided by applicant): Although recent studies have revealed a great deal about the molecular basis of drug addiction, numerous gaps remain in our understanding of the changes in gene expression that are associated with chronic drug intake. One prominent alteration that occurs upon chronic cocaine exposure is accumulation in the striatum of very stable isoforms of the transcription factor d FosB that is produced by alternative splicing of the FosB transcript. The delta FosB isoforms may mediate some of the neural and behavioral modifications that occur with drug addiction. The factors that play a role in the alternative splicing of delta FosB have not yet been identified. To begin to understand the posttranscriptional events that lead to the production of stable dFosB we will test the hypothesis that both cis- and trans-acting factors are important in this regulation. Mutation analysis of FosB will be used to identify the sequences essential for pre-mRNA splicing. Cross-linking and RNA-binding studies will be undertaken to determine which trans-acting factors bind to the RNA regulatory sequences in splicing extracts prepared from tissue culture cells and brains. Factors identified in these studies will be tested in splicing assays to determine if they regulate splicing in vitro. The distribution of the regulatory splicing factors within the brain will be determined using in situ hybridization histochemistry. The expression of the regulatory factors will be changed in order to determine the effect on FosB in vivo. These studies will identify the factors required for the regulation of splicing during chronic cocaine use and lead to an understanding of the mechanisms involved. Because dFosB is also induced by chronic administration of other drugs of abuse, such as amphetamine, nicotine and opiates, the results obtained in this study may also lead to a better understanding of drug addiction.
描述(由申请人提供):尽管最近的研究已经揭示了大量关于药物成瘾的分子基础,但我们对与慢性药物摄入相关的基因表达变化的理解仍有许多空白。慢性可卡因暴露后发生的一个显著变化是,在纹状体中积累了非常稳定的转录因子d FosB同种异构体,这种异构体是由FosB转录物的选择性剪接产生的。FosB亚型可能介导药物成瘾引起的一些神经和行为改变。在delta FosB的选择性剪接中起作用的因素尚未确定。为了开始理解导致稳定dFosB产生的转录后事件,我们将测试顺式和反式作用因子在这种调节中都很重要的假设。FosB的突变分析将用于鉴定前mrna剪接所必需的序列。将进行交联和RNA结合研究,以确定从组织培养细胞和大脑中制备的剪接提取物中哪些反式作用因子与RNA调控序列结合。在这些研究中确定的因素将在剪接试验中进行测试,以确定它们是否调节体外剪接。脑内调节剪接因子的分布将使用原位杂交组织化学确定。调节因子的表达会发生变化,以确定对FosB的体内影响。这些研究将确定在慢性可卡因使用期间调节剪接所需的因素,并导致对所涉及的机制的理解。由于长期服用其他滥用药物,如安非他明、尼古丁和阿片类药物也会诱导dFosB,因此本研究的结果也可能有助于更好地了解药物成瘾。

项目成果

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Judith Ann Potashkin其他文献

Judith Ann Potashkin的其他文献

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{{ truncateString('Judith Ann Potashkin', 18)}}的其他基金

Utilizing gene-level biomarkers of AD to identify pathophysiological mechanisms in human neurons
利用 AD 的基因水平生物标志物识别人类神经元的病理生理机制
  • 批准号:
    10727531
  • 财政年份:
    2023
  • 资助金额:
    $ 23.4万
  • 项目类别:
Network analysis for identifying disease mechanisms and therapeutic targets for dementia
网络分析用于识别痴呆症的疾病机制和治疗靶点
  • 批准号:
    9788248
  • 财政年份:
    2018
  • 资助金额:
    $ 23.4万
  • 项目类别:
Blood RNA biomarkers of Parkinson's disease and progressive supranuclear palsy
帕金森病和进行性核上性麻痹的血液 RNA 生物标志物
  • 批准号:
    9136393
  • 财政年份:
    2016
  • 资助金额:
    $ 23.4万
  • 项目类别:
Cocaine Regulation of FosB Splicing
可卡因对 FosB 剪接的调节
  • 批准号:
    6612675
  • 财政年份:
    2002
  • 资助金额:
    $ 23.4万
  • 项目类别:
Cocaine Regulation of FosB Splicing
可卡因对 FosB 剪接的调节
  • 批准号:
    6506030
  • 财政年份:
    2002
  • 资助金额:
    $ 23.4万
  • 项目类别:
COCAINE REGULATION OF FOSB SPLICING
FOSB 剪接的可卡因监管
  • 批准号:
    6260335
  • 财政年份:
    2000
  • 资助金额:
    $ 23.4万
  • 项目类别:
COCAINE REGULATION OF FOSB SPLICING
FOSB 剪接的可卡因监管
  • 批准号:
    6379099
  • 财政年份:
    2000
  • 资助金额:
    $ 23.4万
  • 项目类别:
FISSION YEAST PREMRNA SPLICING FACTORS
裂变酵母前体RNA剪接因子
  • 批准号:
    2184948
  • 财政年份:
    1992
  • 资助金额:
    $ 23.4万
  • 项目类别:
FISSION YEAST PRE-MRNA SPLICING FACTORS
裂殖酵母前 mRNA 剪接因子
  • 批准号:
    3306992
  • 财政年份:
    1992
  • 资助金额:
    $ 23.4万
  • 项目类别:
FISSION YEAST PRE-MRNA SPLICING FACTORS
裂殖酵母前 mRNA 剪接因子
  • 批准号:
    3306993
  • 财政年份:
    1992
  • 资助金额:
    $ 23.4万
  • 项目类别:

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