Developing an Ex Vivo Model of the Mesolimbic Pathway for Studying Addiction Phenotypes

开发用于研究成瘾表型的中脑边缘通路的体外模型

基本信息

批准号：
10401255
负责人：
Thomas Rudibaugh
金额：
$ 4.2万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2024-04-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401255
关键词：
3-Dimensional Action Potentials Acute Addictive Behavior Affect Animal Experimentation Animal Model Behavior Binding Biological Models Brain CREB1 gene Calcium Carrier Proteins Cell Culture Techniques Cells Cerebrum Characteristics Chronic Cocaine Cocaine Dependence Coculture Techniques Development Dopamine Dopamine Receptor Dose Drug Addiction Drug Targeting Drug abuse Drug usage Dyes Engineering Epigenetic Process Ethics Exposure to Fluorescence Microscopy Gene Expression Generations Genes Genetic Genetic Transcription Goals Hour Human Human Genetics Image Immunohistochemistry In Vitro Intake Lead Link Measures Methods Modeling Modification Molecular Mus Neuronal Plasticity Neurons Organoids Pathway interactions Pharmaceutical Preparations Phenotype Physiological Physiology Property Protocols documentation Rattus Research Research Personnel Rewards Saline Scientist Series Substance abuse problem Substance of Abuse Synapses Synaptic Cleft System Techniques Tissues Up-Regulation Work addiction calcium indicator cell motility cell type cocaine use dopamine transporter dopaminergic neuron drug development drug of abuse expectation human data human model human stem cells in vivo insight interest molecular dynamics nervous system disorder postsynaptic protein biomarkers receptor relating to nervous system response reuptake single-cell RNA sequencing stem cells therapeutic evaluation transcriptome transcriptomics

项目摘要

Project Summary Drug abuse and addiction continues to be a major and growing societal problem. It develops during repeated drug use which causes a series of molecular, transcriptomic, and epigenetic modifications which remodel the neurons in the mesolimbic pathway leading addictive behavior. Despite extensive studies, treatment options remain limited in part because the underlying mechanisms contributing to addictive behavior are still not fully understood. Most previous research to study underlying molecular mechanisms have been performed in animal models specifically mice and rats, which allow scientists to manipulate a specific variable and assess alterations in drug seeking responses. Despite the power of these models, there are limitations to how well mice molecular through tissue physiologies correlate to humans. For example, there are significant differences in the number, cell type compositions, and functions of their respective mesolimbic pathway neurons. Therefore, there is a need for ex vivo model systems which capture the human genetic, epigenetic, transcriptional, and multicellular properties of mesolimbic cell types and connections. We will contribute to this goal by differentiating human stem cells into organoids containing dopaminergic and medium spiny neurons of the mesolimbic pathway and generate functional synapses between the two. The model will be interrogated by exposing the cultured neurons to cocaine and studying their molecular, transcriptional, and epigenetic responses and comparing these responses to available mice and human data. With this model, we can further understand the key underlying mechanisms that contribute to addiction formation potentially leading to specific targets for drug development.

项目摘要毒品滥用和成瘾仍然是一个重大的社会问题。它在反复使用期间发展引起一系列分子，转录组和表观遗传学修饰，这些修饰重塑了神经元中唇途径引导上瘾行为。尽管进行了广泛的研究，但治疗方案仍然有限因为导致成瘾行为的基本机制仍然没有完全理解。大多数研究了研究基本分子机制的研究已在动物模型中进行，专门针对小鼠和大鼠，这使科学家可以操纵特定的变量并评估寻求药物反应的变化。尽管有这些模型的功能，通过组织生理学的小鼠分子与人类相关的分子的局限性存在局限性。例如，它们的数量，细胞类型组成及其功能存在显着差异中边途径神经元。因此，需要捕获人遗传的离体模型系统，中边细胞类型和连接的表观遗传学，转录和多细胞特性。我们将为通过将人类干细胞区分为含有多巴胺能和中刺神经元的类器官中边路途径并在两者之间产生功能突触。该模型将通过公开培养的神经元可卡因并研究其分子，转录和表观遗传反应，并将其比较对可用的小鼠和人类数据的响应。使用此模型，我们可以进一步了解关键的潜在机制这有助于成瘾形成可能导致药物开发的特定目标。