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

产品说明：K 02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，以进行NIDA资助的药物滥用-HIV-1合并症研究，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HIV-1是具有可怕后果的相互关联的流行病。为了解决这个问题，候选人指导赠款R 01 DA 018633，“阿片类药物-HIV诱导的神经变性的机制”和R 01 DA 033200“纹状体中HIV和阿片类药物导向的突触树突损伤/死亡的调节”，并且是R 01 DA 034231“HIV和阿片类药物驱动的突触树突损伤的神经胶质起源”的多个PI，并且是其他赠款的共同负责人和许多其他项目的顾问。申请人已发表了开创性研究，证明：阿片类药物可直接影响CNS成熟;阿片类药物受体的细胞基础和星形胶质细胞和少突胶质细胞中的功能;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神经胶质细胞类型中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并发症的方法，指导了非常成功的博士前和博士后，基础和临床教师;包括负责任的研究行为（RCR）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。K 02奖将使候选人能够：（1）追求目前赠款的目标，同时制定尖端的药物滥用方法（例如，全细胞膜片钳电生理学），以评估阿片和HIV相互作用的突触树突损伤的触发事件）和更好的物质滥用模型（自我给药）。(2)通过使用工程化HIV前病毒载体作为新来源的非感染性HIV/“病毒毒素”的转化研究合并基础和临床方法，用于研究旁观者神经元中的电生理学效应，并采用CRISPR（成簇规则间隔短回文重复序列），这是一种基因组编辑策略，其目标是完全消除或添加受体基因（例如，OPRM 1）。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）。他被部门招募到VCU。药理学和毒理学的追求这些目标，并得到了巨大的支持，这一奋进。

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.