Role of System xc- in Addiction: Developing & Phenotyping a Slc7a11 knockout rat

系统 xc- 在成瘾中的作用:发展

基本信息

  • 批准号:
    8608513
  • 负责人:
  • 金额:
    $ 26.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-02-01 至 2016-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Abnormal glutamate signaling within corticostriatal pathways has been linked to craving in humans and cocaine seeking in rats. Unfortunately, our limited understanding of glutamate has contributed to the lack of effective, well-tolerated treatments for many CNS diseases, including drug addiction. While glutamate is described as the primary excitatory neurotransmitter in the brain, it is unclear how the many components of this complex network of transporters and release mechanisms function in an integrated manner to regulate excitatory signaling. Due to a lack of available tools that selectively target these novel mechanisms, it has been difficult to convincingly demonstrate the importance of these novel mechanisms. One such component is system xc-, a source of nonvesicular glutamate release that is primarily expressed on astrocytes. It functions by exchanging extracellular cysteine for intracellular glutamate. System xc influences synaptic activity and plasticity through the release of glutamate and dopamine in multiple brain regions. Repeated cocaine produces a persistent reduction in system xc- activity, which appears to be necessary for glutamate-induced compulsive drug seeking. In contrast, manipulations that prevent or reverse cocaine-induced changes in system xc- activity normalize glutamate levels and blunt cocaine-induced reinstatement. In humans, N-acetylcysteine has shown promise in the treatment of drug addiction and related compulsive disorders. Studies such as these indicate that system xc- function may have profound implications in revealing the cellular basis of addiction, as well as the role of astrocytes in central nervous system activity - especially if it is determined that system xc- is the primary mechanism of action for N-acetylcysteine. Efforts to manipulate system xc- in rats typically involve the use of pharmacological tools that are associated with predictable pharmacological concerns. Increasing system xc activity by direct infusion of cystine into the brain or systemic administration of a cysteine prodrug (e.g., N acetylcysteine) are both effective since the rate of cysteine-glutamate exchange is a function of the relative extracellular/intracellular concentration gradients of its substrates. Mutations in the gene giving rise to xCT, the active subunit for system xc, is present in multiple mouse strains. However, essentially every study linking system xc to glutamate homeostasis or addiction has been conducted in rats or primates. The goal of this proposal is to use the novel Zinc Finger Nucleases (ZFN) approach to mutate the Slc7a11 gene encoding xCT in rat. After creating an xCT deficient rat model (aim 1), we will verify and characterize the general phenotype (aim 2) as well as addiction-specific phenotypes (aim 3). The development and application of these technologies to generate transgenic rat strains may result in a major paradigm shift in studying the neural basis of addiction by enabling more sophisticated and highly specific manipulations in a species that better models critical aspects of human addiction.
描述(由申请人提供):皮质纹状体通路内的异常谷氨酸信号传导与人类的渴望和大鼠的可卡因寻找有关。不幸的是,我们对谷氨酸的了解有限,导致许多中枢神经系统疾病(包括毒瘾)缺乏有效、耐受性良好的治疗方法。虽然谷氨酸被描述为大脑中主要的兴奋性神经递质,但目前尚不清楚这个复杂的转运蛋白网络的许多成分和释放机制如何以整合的方式发挥作用来调节兴奋性信号传导。由于缺乏选择性地针对这些新机制的可用工具,很难令人信服地证明这些新机制的重要性。其中一个组件是系统 xc-,它是主要在星形胶质细胞上表达的非囊泡谷氨酸释放源。它通过将细胞外的半胱氨酸交换为细胞内的谷氨酸来发挥作用。系统 xc 通过以下方式影响突触活动和可塑性 多个大脑区域释放谷氨酸和多巴胺。反复吸食可卡因会导致系统 xc 活性持续降低,这似乎是谷氨酸诱导的强迫性药物寻求所必需的。相反,防止或逆转可卡因引起的系统xc活性变化的操作可使谷氨酸水平正常化并减弱可卡因引起的恢复。在人类中,N-乙酰半胱氨酸在治疗药物成瘾和相关强迫症方面显示出良好的前景。诸如此类的研究表明,xc-系统的功能可能对揭示成瘾的细胞基础以及星形胶质细胞在中枢神经系统活动中的作用具有深远的影响——特别是如果确定xc-系统是N-乙酰半胱氨酸的主要作用机制的话。 在大鼠中操纵系统 xc- 的努力通常涉及使用与可预测的药理学问题相关的药理学工具。通过直接将胱氨酸输注到大脑中或全身施用半胱氨酸前药(例如,N乙酰半胱氨酸)来增加系统xc活性都是有效的,因为半胱氨酸-谷氨酸交换速率是其底物的相对细胞外/细胞内浓度梯度的函数。基因突变 xCT 是系统 xc 的活性亚基,存在于多种小鼠品系中。然而,基本上每一项将 xc 系统与谷氨酸稳态或成瘾联系起来的研究都是在大鼠或灵长类动物身上进行的。该提案的目标是使用新型锌指核酸酶 (ZFN) 方法来突变大鼠中编码 xCT 的 Slc7a11 基因。创建 xCT 缺陷大鼠模型(目标 1)后,我们将验证并表征一般表型(目标 2)以及成瘾特异性表型(目标 3)。开发和应用这些技术来产生转基因大鼠品系,可能会导致研究成瘾神经基础的重大范式转变,通过在物种中进行更复杂和高度特异性的操作,更好地模拟人类成瘾的关键方面。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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DAVID A BAKER其他文献

DAVID A BAKER的其他文献

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{{ truncateString('DAVID A BAKER', 18)}}的其他基金

PACAP-Dependent Coordination of Glutamate Signaling between Neurons and Astrocytes
神经元和星形胶质细胞之间谷氨酸信号传导的 PACAP 依赖性协调
  • 批准号:
    10053148
  • 财政年份:
    2020
  • 资助金额:
    $ 26.39万
  • 项目类别:
PACAP-Dependent Coordination of Glutamate Signaling between Neurons and Astrocytes
神经元和星形胶质细胞之间谷氨酸信号传导的 PACAP 依赖性协调
  • 批准号:
    10402872
  • 财政年份:
    2020
  • 资助金额:
    $ 26.39万
  • 项目类别:
PACAP-Dependent Coordination of Glutamate Signaling between Neurons and Astrocytes
神经元和星形胶质细胞之间谷氨酸信号传导的 PACAP 依赖性协调
  • 批准号:
    10612429
  • 财政年份:
    2020
  • 资助金额:
    $ 26.39万
  • 项目类别:
Glucocorticoid regulation of dopamine clearance, cocaine seeking, and reward
糖皮质激素对多巴胺清除、可卡因寻求和奖励的调节
  • 批准号:
    8720462
  • 财政年份:
    2014
  • 资助金额:
    $ 26.39万
  • 项目类别:
Glucocorticoid regulation of dopamine clearance, cocaine seeking, and reward
糖皮质激素对多巴胺清除、可卡因寻求和奖励的调节
  • 批准号:
    9061043
  • 财政年份:
    2014
  • 资助金额:
    $ 26.39万
  • 项目类别:
Glucocorticoid regulation of dopamine clearance, cocaine seeking, and reward
糖皮质激素对多巴胺清除、可卡因寻求和奖励的调节
  • 批准号:
    8920526
  • 财政年份:
    2014
  • 资助金额:
    $ 26.39万
  • 项目类别:
Role of System xc- in Addiction: Developing & Phenotyping a Slc7a11 knockout rat
系统 xc- 在成瘾中的作用:发展
  • 批准号:
    8463353
  • 财政年份:
    2013
  • 资助金额:
    $ 26.39万
  • 项目类别:
Targeting System Xc- for the Treatment of Addiction
用于治疗成瘾的靶向系统 Xc-
  • 批准号:
    7737627
  • 财政年份:
    2009
  • 资助金额:
    $ 26.39万
  • 项目类别:
Targeting System Xc- for the Treatment of Addiction
用于治疗成瘾的靶向系统 Xc-
  • 批准号:
    7894918
  • 财政年份:
    2009
  • 资助金额:
    $ 26.39万
  • 项目类别:
Targeting System Xc- for the Treatment of Schizophrenia
靶向系统 Xc- 用于治疗精神分裂症
  • 批准号:
    8397352
  • 财政年份:
    2008
  • 资助金额:
    $ 26.39万
  • 项目类别:

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  • 批准号:
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  • 批准号:
    10619173
  • 财政年份:
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High dose acetaminophen with n-acetylcysteine rescue as a novel STAT3 inhibitor with anti-cancer stem cell properties
高剂量对乙酰氨基酚与 n-乙酰半胱氨酸救援作为具有抗癌干细胞特性的新型 STAT3 抑制剂
  • 批准号:
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N-乙酰半胱氨酸治疗酒精使用障碍的随机对照试验
  • 批准号:
    nhmrc : 2001375
  • 财政年份:
    2021
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    $ 26.39万
  • 项目类别:
    Clinical Trials and Cohort Studies Grants
High dose acetaminophen with n-acetylcysteine rescue as a novel STAT3 inhibitor with anti-cancer stem cell properties
高剂量对乙酰氨基酚与 n-乙酰半胱氨酸救援作为具有抗癌干细胞特性的新型 STAT3 抑制剂
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N-乙酰半胱氨酸促进骨愈合作用的考察
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