Neuron-Glia Mechanisms & Interactions Underlying Opioid Abuse-HIV-1 Comorbidity

描述：K02独立科学家奖将使候选人在弗吉尼亚联邦大学（VCU）获得最大限度的保护时间，以从事NIDA资助的药物滥用- hiv -1共病的研究，获得先进的跨学科专业知识，并指导该领域的学生和教师科学家。药物滥用和艾滋病毒-1是相互关联的流行病，具有可怕的后果。为了解决这个问题，候选人主持了R01 DA018633，“阿片类药物HIV诱导的神经变性机制”和R01 DA033200，“艾滋病毒和阿片类药物导向的突触树突损伤/死亡的调节”，并且是R01 DA034231，“艾滋病毒和阿片类药物驱动的突触树突损伤的胶质起源”的多个pl，并且是其他许多项目的合作人和顾问。申请人发表的开创性研究表明：阿片类药物可以直接影响中枢神经系统的成熟；星形胶质细胞和少突胶质细胞中阿片受体的细胞基础及其功能阿片类药物本质上加剧了神经艾滋病的发病机制，确定了神经元和多种胶质细胞类型的细胞内和细胞间病理机制。申请人建立了全球合作，继续优化阿片类药物滥用- hiv -1合并症的方法，指导了非常成功的博士后，基础和临床教师；包括负责任的研究行为（RCR）方面的培训，共同指导了NIDA培训补助金，并组织了促进药物滥用研究的地方和国际会议。K02奖将使候选人能够：（1)追求当前资助的目标，同时开发药物滥用的前沿方法（例如，全细胞膜片钳电生理学），以评估阿片类药物和艾滋病毒相互作用突触树突损伤的触发事件）和更好的药物滥用模型（自我给药）。(2)通过转化研究，将基础和临床方法结合起来，利用工程HIV前病毒载体作为一种新的非感染性HIV/“病毒毒素”来源，研究旁观者神经元的电生理效应，并采用crispr（聚集规律间隔的短回文重复序列）这一基因组编辑策略，目的是完全消除或添加受体基因（如OPRM1）。候选人将继续指导学生/早期职业科学家（包括代表性不足的个人，并强调RCR）。他被VCU的药理学和毒理学部门招募来追求这些目标，并得到了巨大的支持。

DESCRIPTION: A K02 independent Scientist Award will enable the candidate to obtain maximally protected time at Virginia Commonwealth University (VCU) to pursue NIDA funded research on substance abuse-HIV-1 comorbidity, acquire advanced cross-disciplinary expertise, and to mentor student and faculty scientists in this area. Drug abuse and HIV-1 are interlinked epidemics with horrific consequences. To address this problem, the candidate directs grants R01 DA018633, "Mechanisms of opiate drug-HIV-induced neurodegeneration" and R01 DA033200 "Regulation of HIV and opiate-directed synaptodendritic injury/death in striatum", and is a multi-Pl on R01 DA034231 "Glial origins of HIV and opiate-driven synaptodendritic injury", and is a co-l on other grants and consultant on numerous other projects. The applicant has published seminal studies demonstrating: that opioids can directly affect CNS maturation; the cellular basis of opioid receptor and function in astrocytes and oligodendrocytes; and that opioids intrinsically exacerbate the pathogenesis of neuroAIDS-identifying both intra- and intercellular pathologic mechanisms in neurons and multiple glial types. The applicant has established worldwide collaborations that continue to optimize approaches to opioid abuse-HIV-1 comorbidity, has mentored highly successful pre- and postdoctoral, and basic and clinical faculty; including training in the responsible conduct of research (RCR), has co-directed a NIDA training grant, and organized local and international conferences promoting substance abuse research. A K02 award will enable the candidate to: (1) pursue the goals of current grants, while developing cutting-edge approaches to substance abuse (e.g., whole-cell patch-clamp electrophysiology) to assess the trigger events underlying opiate and HIV interactive synaptodendritic injury) and better models of substance abuse (self-administration). (2) To merge basic and clinical approaches through translational research using engineered HIV proviral vectors as a novel source non-infectious HIV/"virotoxins" for studying electrophysiological effects in bystander neurons and to adopt CRISPRs (clustered regularly interspaced short palindromic repeats), a genome editing strategy, with the goal of completely eliminating or adding receptor genes (e.g., OPRM1). The candidate will continue to mentor students/early career scientists (including under-represented individuals and with an emphasis on RCR). He was recruited to VCU by the Dept. of Pharmacology and Toxicology to pursue these goals and receives tremendous support for this endeavor.