A novel role for Oligodendrocyte Progenitor Cells (OPC) in opiate addiction

少突胶质祖细胞 (OPC) 在阿片成瘾中的新作用

• 批准号: 9979987
• 负责人: Jennifer Martin
• 金额: $ 7.18万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2020-07-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979987
• 关键词: Adult; Affinity Chromatography; Animal Model; Area; Asses; Award; Behavior; Behavioral; Behavioral Mechanisms; Brain; Brain Diseases; CSPG4 gene; Cell Differentiation process; Cell Lineage; Cells; Chromatin Remodeling Factor; Chronic; Critical Thinking; Data; Development; Disease; Dopamine; Drug Addiction; Epidemic; Faculty; Family; Fellowship; Financial Hardship; Funding; Gene Expression; Gene Transfer; Genetic; Genetic Transcription; Goals; Heroin; Heroin Dependence; Human; Institution; Intake; Lead; Maintenance; Major Depressive Disorder; Mediating; Mediator of activation protein; Mental disorders; Mentors; Methods; Molecular; Motivation; Mus; Myelin; Neuraxis; Neurobiology; Neuroglia; Neurons; Oligodendroglia; Opiate Addiction; Opioid; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiology; Play; Population; Positioning Attribute; Postdoctoral Fellow; Pre-Clinical Model; Prefrontal Cortex; Proliferating; Property; Public Health; Public Speaking; RNA; Recurrent disease; Regulation; Relapse; Replacement Therapy; Research; Research Personnel; Rewards; Ribosomes; Role; SMARCA4 gene; Saline; Schizophrenia; Self Administration; Structure; Substance abuse problem; System; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Transcript; Translating; Viral; Writing; addiction; behavioral plasticity; cell type; chromatin remodeling; comorbidity; design; disorder later incidence prevention; drug of abuse; gene therapy; insight; interest; member; mesolimbic system; motivated behavior; mouse model; nerve stem cell; neuroadaptation; new therapeutic target; novel; oligodendrocyte precursor; oligodendrocyte progenitor; pre-doctoral; preclinical study; precursor cell; progenitor; reinforcer; skills; stem cell differentiation; stem cells; transcription factor; transcriptome; transcriptome sequencing; transcriptomics

Project Summary / Abstract Heroin addiction is a chronic brain disease that is characterized by compulsive drug intake despite the presence of negative consequences. Heroin addictions have a lifelong vulnerability to relapse, in part due to heightened motivation to seek the drug. Unfortunately, pharmacotherapies for heroin addiction remain limited and largely ineffective. In order to identify novel therapeutic targets to aid in the prevention of relapse, the molecular mechanism of behaviors leading to relapse, specifically motivation, must be better understood. It is known that drugs of abuse induce plasticity in key regions of the mesolimbic dopamine system, including the prefrontal cortex (PFC). Specifically, alterations within this region have been associated with the maladaptive behaviors associated with addiction, including motivation for drug reinforcers, which can be assed using a progressive ratio test in both the human condition and animal models of addiction. While many of the cellular adaptions induced by heroin have predominately focused on the neuronal cells within the PFC, our preliminary data, presented in Aim 1, has identified a dysregulation in glial cells, and specifically oligodendrocytes, following heroin self-administration, an animal model of addiction. I have shown that a transcription factor key in the regulation of oligodendrocyte progenitor cell (OPC) differentiation, Sox10, is upregulated in the PFC following heroin self-administration via chromatin remodeler BRG1. Furthermore, I have identified Sox10 as a critical mediator in a hallmark behavior associated with addiction, motivation to seek the drug. While these novel studies have added to our understanding of the role of glial transcripts in the addicted state, the changes that are occurring specifically in progenitor population, versus cells of the whole lineage, remain unknown. Therefore, I am proposing to examine cellular changes in a specific subtype of OPCs, NG2+ cells, which have distinct physiology properties from other glial cells. My central hypothesis in Aim 2 is that heroin induces transcriptomic changes within the NG2+ cells in the PFC compared to saline controls. I will determine the cell-type specific alterations in genes transcription in this subset of cells using genetic mouse models combined with viral-mediated gene transfer to selectively purify RNA from NG2 cells using Translating Ribosomal Affinity Purification (TRAP). The RNA will be analyzed for transcript changes using RNA-sequencing. Scientifically, this proposal will establish a critical role for NG2 cells in the heroin-addicted state. While these studies are underway, I will participate in a multifaceted Training Plan designed to develop the non-bench skills necessary to reach my ultimate goals of becoming a tenured faculty in an academic setting. In addition, Aim 3 was designed to aid in the identification of a well-funded postdoctoral mentor who continue to help me develop the skills necessary to transition from a postdoctoral scholar to an independent researcher at a research intensive institution, which will include receiving my own funding through a K99 award.

项目摘要 /摘要 海洛因成瘾是一种慢性脑疾病，尽管有强迫性药物的特征 存在负面后果。海洛因成瘾存在终身复发的脆弱性，部分原因是 提高了寻求药物的动力。不幸的是，海洛因成瘾的药物治疗仍然有限 并且在很大程度上无效。为了确定新的治疗靶标，以帮助预防复发， 必须更好地理解导致复发，特别是动机的行为的分子机制。这是 知道滥用药物会引起中唇多巴胺系统的关键区域的可塑性，包括 前额叶皮层（PFC）。具体而言，该区域内的改变与适应不良有关 与成瘾相关的行为，包括药物增强剂的动机，可以使用 人类状况和动物成瘾模型中的渐进率检验。而许多细胞 海洛因引起的适应性主要集中在PFC内的神经元细胞上 在AIM 1中介绍的数据已经确定了神经胶质细胞的失调，特别是少突胶质细胞的失调 继海洛因自我管理之后，是成瘾的动物模型。我已经证明了转录因子密钥 在调节少突胶质细胞祖细胞（OPC）分化中，SOX10在PFC中上调 通过染色质改造BRG1进行海洛因自我给药后。此外，我已经将Sox10确定为 与成瘾相关的标志性行为，寻求药物的动力。而这些 新的研究增加了我们对神经胶质转录本在上瘾状态的作用的理解，这些变化 专门发生在祖细胞种群中，整个谱系的细胞与整个谱系的细胞相比，尚不清楚。 因此，我建议检查OPC的特定亚型NG2+细胞中的细胞变化，这些细胞具有 来自其他神经胶质细胞的不同生理特性。我在目标2中的中心假设是海洛因引起的 与盐水对照组相比，PFC中NG2+细胞内的转录组发生变化。我将确定 使用遗传小鼠模型组合的基因转录中基因转录的细胞类型特异性变化 病毒介导的基因转移以选择性地纯化NG2细胞中的RNA，使用核糖体亲和力 纯化（陷阱）。 RNA将使用RNA测序分析转录本的变化。从科学上讲 该提案将在海洛因成瘾状态下为NG2细胞确定至关重要的作用。这些研究是 正在进行中，我将参加一项旨在发展必要的非基础技能的多面培训计划 为了实现在学术环境中成为终身教师的最终目标。此外，AIM 3是 旨在帮助识别资金丰富的博士后导师，他们继续帮助我发展 从博士后学者过渡到研究密集的独立研究人员所需的技能 机构将包括通过K99奖获得我自己的资金。