Targeting Phospholipase C and Dendritic Spines to Reduce Cocaine and Heroin Motivation

靶向磷脂酶 C 和树突棘以减少可卡因和海洛因动机

基本信息

批准号：
10373990
负责人：
Ethan Michael Anderson
金额：
$ 18.85万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373990
关键词：
Addictive Behavior Adult Advisory Committees Behavior Behavioral Behavioral Model Binding Biochemical Biological Brain Brain region Brain-Derived Neurotrophic Factor Cells Chronic Cloning Cocaine Data Dendritic Spines Development Doctor of Philosophy Drug Addiction Drug abuse Drug usage Faculty Future Generations Goals Grant Guanosine Triphosphate Phosphohydrolases Heroin Heroin Dependence Human Individual Institutes Knowledge Learning LoxP-flanked allele Mediating Medical Mentors Molecular Molecular Biology Molecular Cloning Molecular Neurobiology Morphology Motivation Neurobiology Neuronal Plasticity Neurons Nucleus Accumbens PLC gamma1 Paper Patients Pharmaceutical Preparations Phospholipase Phospholipase C Phospholipase C Signaling Pathway Play Positioning Attribute Process Protein Kinase C Protein Tyrosine Kinase Publications Publishing Rattus Research Research Personnel Rewards Role Scientist Self Administration Signal Pathway Signal Transduction South Carolina Spinal Manipulation Substance Use Disorder Synapses System Techniques Technology Testing Therapeutic Training Training Programs Transgenic Organisms Universities Validation Vertebral column Viral Viral Vector Work addiction adeno-associated viral vector base brain morphology career career development cell type cocaine self-administration density drug of abuse drug seeking behavior heroin use in vivo innovation knock-down meetings novel opioid use optogenetics overexpression programs receptor recombinant virus skills small hairpin RNA symposium tool vector

项目摘要

This grant will establish new independent investigator studies on maladaptive neuroplasticity induced by chronic use of the addictive drugs cocaine and heroin. This project will be led by Ethan Anderson, Ph.D.; an energetic, passionate, and productive researcher on a trajectory to develop an independent research position studying drug addiction. This project will take place at the Medical University of South Carolina (MUSC), an institute with a stellar reputation for producing high quality researchers that specialize in drug addiction. Dr. Anderson will be mentored Dr. Chris Cowan and Dr. Peter Kalivas at MUSC. These mentors have successfully trained scientists who have gone on to faculty positions at major universities and are experts in behavioral models of drug addiction, biochemical, molecular, and structural changes in the brain due to chronic drug use, and the generation of novel tools to investigate these mechanisms of addiction. This overall project will employ 2 novel and innovative approaches to investigate and reverse the negative effects of both cocaine and heroin on morphological and behavioral changes underlying addiction. The short-term goals of this project involve 2 aims: 1) Determine the intracellular mechanism of a novel, endogenous anti-addictive signaling pathway through and phospholipase Cᵧ1 (PLC) as a potential new target for reducing opioid use in humans. 2) Reverse cocaine-induced maladaptive changes in synapses in the nucleus accumbens by selectively targeting and optogenetically removing dendritic spines recently activated by cocaine. This will determine whether a direct causal relationship exists between reversal of these morphological brain changes and alterations in addictive behavior. The scientific training program for Dr. Anderson will focus on learning 3 new skills: 1) optogenetics with novel in vivo spine reduction technology, 2) heroin self-administration behavior, and 3) cloning and molecular biological techniques necessary for constructing novel viral vectors. In addition, Dr. Anderson will receive excellent career development training via an outstanding career advisory committee (Drs. Eric Nestler, David Self, Arthur Riegel, and Jacqueline McGinty) and specific individual career training from Drs. Cowan and Kalivas. The individual scientific training will include individual meetings with his mentors to discuss and prepare future R01 applications, presentations at seminars and 1-2 conferences per year, the publication of 1 paper every 1-2 years, and didactic course work in drug addiction and cutting-edge molecular biology. This grant will pave the way for Dr. Anderson to achieve his potential to become a productive, R01 fundable, independent scientist in the field of addiction research by allowing him to learn new scientific skills, produce high-impact data, receive excellent and broad-based training with expertise from his advisors and mentors, and study in the exceptional training grounds of MUSC.

该赠款将建立新的独立研究者研究，研究由长期使用可卡因和海洛因的添加剂。该项目将由博士Ethan Anderson领导；一个充满活力，热情和产品研究人员在轨迹上建立独立的研究职位研究吸毒成瘾。该项目将在南卡罗来纳州医科大学（MUSC）举行，在培养专门研究吸毒的高质量研究人员方面享有盛誉的学院。博士安德森（Anderson）将在MUSC修复Chris Cowan博士和Peter Kalivas博士。这些换人已经成功训练有素的科学家，他们一直担任大型大学的教师职务，并且是行为专家由于慢性药物使用而导致的药物成瘾模型，生化，分子和结构变化，以及研究这些成瘾机制的新型工具。这个整体项目将采用 2新颖和创新的方法来调查和扭转可卡因和海洛因的负面影响关于成瘾的形态和行为变化。该项目的短期目标涉及2 目的：1）确定新型内源性抗可吸引力通路的细胞内机制通过和磷脂酶Cᵧ1（PLC）是减少人类阿片类药物使用的潜在新目标。 2）反向可卡因诱导的通过选择性靶向和可卡因最近激活的光源性去除树突状棘。这将确定是否直接这些形态学大脑变化的逆转与添加剂的变化之间存在因果关系行为。安德森博士的科学培训计划将专注于学习3个新技能：1）光遗传学通过新颖的体内脊柱减少技术，2）海洛因自我给药行为，以及3）克隆和构建新型病毒载体所需的分子生物学技术。此外，安德森博士将通过出色的职业咨询委员会获得出色的职业发展培训（Eric Nesler博士， David Self，Arthur Riegel和Jacqueline McGinty和Drs的特定个人职业培训。 Cowan和卡利瓦斯。个别的科学培训将包括与他的导师进行讨论的个人会议，准备未来的R01申请，下水道的演示和每年1-2次会议，出版1 每1 - 2年的纸张纸，并在药物成瘾和尖端的分子生物学方面工作。这格兰特（Grant）将为安德森博士（Anderson）博士铺平道路成瘾研究领域的独立科学家通过允许他学习新的科学技能，生产新的科学技能高影响数据，接受顾问和导师的专业知识，获得出色和广泛的培训，以及在MUSC的非凡培训理由上进行研究。