Domain- and protein-selective BET mechanisms in cocaine-seeking behaviors

可卡因寻求行为中的结构域和蛋白质选择性 BET 机制

• 批准号: 10714343
• 负责人: Gregory Charles Sartor
• 金额: $ 45.47万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714343
• 关键词: Abstinence; Address; Affinity; Area; Attenuated; BRD2 gene; Behavior; Behavioral; Binding; Binding Sites; Brain Diseases; Bromodomain; Bromodomains and extra-terminal domain inhibitor; Clinical; Co-Immunoprecipitations; Cocaine; Cocaine use disorder; DNA Binding; Data; Disease model; Economics; Epigenetic Process; Extinction; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Histone Acetylation; Histones; Individual; Injections; Laboratories; Link; Mass Spectrum Analysis; Mediating; Modeling; Nucleus Accumbens; Peptoids; Pharmaceutical Preparations; Pharmacotherapy; Play; Procedures; Protein Family; Proteins; Proteomics; Reader; Regulation; Research; Role; Self Administration; Substance Use Disorder; Techniques; Tertiary Protein Structure; Testing; Therapeutic; Viral; addiction; behavioral response; cell type; clinically relevant; cocaine relapse; cocaine seeking; cocaine self-administration; cocaine use; drug of abuse; drug seeking behavior; experimental study; inhibitor; insight; member; multiple omics; neurobehavioral; new therapeutic target; novel; novel strategies; pharmacologic; prevent; response; side effect; single-cell RNA sequencing; small molecule; substance use treatment; therapeutic target; tool; transcriptomics; translational applications

Project Summary Epigenetic pharmacotherapy for substance use disorder (SUD) is a rapidly expanding area of research. With the ability to bind to acetylated histones and regulate drug-induced transcriptional adaptations, members of the bromodomain and extra-terminal domain (BET) family of proteins (BRD2, BRD3, BRD4 and BRDT) have emerged as promising therapeutic targets. To date, however, only pan-BET bromodomain inhibitors, small molecules that bind to both bromodomains (BD1 and BD2) within all BET proteins, have been tested in SUD- related experiments. The use of these non-selective pharmacological inhibitors in SUD models limits our mechanistic understanding of individual BET proteins, bromodomain-selective functions (BD1 vs. BD2), and non- bromodomain BET interactions that regulate drug-induced neurobehavioral adaptations. New evidence from our laboratory indicates that selectively targeting individual BET domains and proteins is a novel and effective strategy to reduce cocaine-induced behavioral and transcriptional responses without causing sides effects observed with pan-BET inhibitors. To build on these exciting data and to advance the field of epigenetic pharmacotherapy for SUD, we propose to use highly selective, clinically relevant treatments, viral-mediated approaches, and multiomic analysis to investigate domain- and protein-specific mechanisms of BET proteins during cocaine-seeking behaviors. To achieve these goals, we will first investigate the behavioral and cell type- specific transcriptomic responses of domain-selective BET inhibitors in cocaine economic demand and reinstatement procedures. Next, using co-immunoprecipitation and mass-spectrometry, we will characterize BRD4 interactome changes following short- and intermittent-access cocaine self-administration, and in functional studies, we will use newly developed tools to identify a role for non-bromodomain mechanisms of BRD4 in cocaine self-administration. Finally, we will interrogate novel transcriptional and behavioral roles for BRD2 in cocaine-seeking behaviors. Together, these experiments will provide significant contributions to the field of addiction epigenetics as well as novel therapeutic targets to reduce cocaine use and relapse.

项目概要 物质使用障碍（SUD）的表观遗传药物疗法是一个快速扩展的研究领域。随着 与乙酰化组蛋白结合并调节药物诱导的转录适应的能力， 溴结构域和末端外结构域 (BET) 蛋白家族（BRD2、BRD3、BRD4 和 BRDT）具有 成为有希望的治疗靶点。然而，迄今为止，只有泛 BET 溴结构域抑制剂、小型 与所有 BET 蛋白中的溴结构域（BD1 和 BD2）结合的分子已在 SUD- 中进行了测试 相关实验。在 SUD 模型中使用这些非选择性药物抑制剂限制了我们的研究 对单个 BET 蛋白、溴结构域选择性功能（BD1 与 BD2）和非 溴结构域 BET 相互作用调节药物诱导的神经行为适应。来自我们的新证据 实验室表明选择性靶向单个 BET 结构域和蛋白质是一种新颖且有效的方法 减少可卡因诱导的行为和转录反应而不引起副作用的策略 用 pan-BET 抑制剂观察到。以这些令人兴奋的数据为基础并推进表观遗传学领域 对于 SUD 的药物治疗，我们建议使用高度选择性的、临床相关的治疗、病毒介导的治疗 方法和多组学分析来研究 BET 蛋白的域和蛋白特异性机制 在寻求可卡因的行为期间。为了实现这些目标，我们将首先研究行为和细胞类型- 域选择性 BET 抑制剂在可卡因经济需求中的特异性转录组反应 恢复程序。接下来，我们将使用免疫共沉淀和质谱来表征 短期和间歇性可卡因自我给药后 BRD4 相互作用组发生变化，并且在功能方面也发生变化 研究中，我们将使用新开发的工具来确定 BRD4 的非溴结构域机制在 可卡因自我给药。最后，我们将探讨 BRD2 在 寻求可卡因的行为。总之，这些实验将为该领域做出重大贡献 成瘾表观遗传学以及减少可卡因使用和复发的新治疗靶点。