Development of gene transfer approaches for neuroAIDS

神经艾滋病基因转移方法的开发

• 批准号: 6938523
• 负责人: YUANAN LU
• 金额: $ 29.06万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6938523
• 关键词: AIDS dementia complex; AIDS therapy; Adenoviridae; cell migration; clinical research; defective virus; feline immunodeficiency virus; gene therapy; genetic transduction; human immunodeficiency virus 1; human tissue; laboratory mouse; laboratory rat; macrophage; microglia; monocyte; neurotoxins; neurotrophic factors; simian immunodeficiency virus; technology /technique development; tissue /cell culture; transfection /expression vector

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) is a primary disorder of the central nervous system (CNS) that affects about 20% of individuals infected with HIV. Treatment for HIVD are limited, in part because many antiretroviral drugs fail to penetrate the blood-brain barrier (BBB); novel approaches are therefore needed. One such approach may be to target cells that normally traffic across the BBB- such as blood monocytes. The hypothesis of this proposal is that it may be possible to genetically modify bolld monocytes and to use them as a "Trojan horse" delivery system, to effect gene transfer into the CNS, for treatment of neuroAIDS. This project will be conducted as an integrated, coordinated collaboration between investigators at the University of Hawaii and the University of Rochester. The applicant component of this project will focus on the testing and comparative analysis of different virus vectors for their potential ability to transduce blood monocytes; vectors will also be evaluated with respect to their efforts on monocyte transmigration across the blood-brain barrier. Experiments will also be conducted to determine (1) whether monocytes transduced with a defective interfering lentivirus vector (DLV) are less permissive for replication of infectious HIV-1, and (2) whether the DLV can be mobilized, amplified and spread to untransduced bystander cells by infectious HIV-1. The collaborator component of this application will focus on analyzing whether vector-transduced monocytes release soluble neurotoxic factors associated with cellular activation. In addition, the collaborator with construct a virus vector encoding a soluble neuroprotective factor, and will determine if monocytes transduced with this vector are capable of promoting the survival of bystander neurons exposed to well-defined candidate HIV- neurotoxins. The entire project comprises a tightly integrated whole, and will allow for the complementary expertise of the investigators to be applied in a maximally productive and mutually beneficial way. The collaboration will also provide ample opportunitites for the PI, and his students and fellows, to obtain training in neuroscience and a wide range of related techniques. Overall, the work is expected to result in significant insight into new approaches for treatment of neuroAIDS and other neurologic diseases.

描述（由申请人提供）： 人类免疫缺陷病毒 (HIV) 是一种主要的中枢神经系统 (CNS) 疾病，影响约 20% 的 HIV 感染者。 HIVD 的治疗有限，部分原因是许多抗逆转录病毒药物无法穿透血脑屏障 (BBB)；因此需要新的方法。 一种这样的方法可能是针对通常穿过血脑屏障的细胞，例如血液单核细胞。该提议的假设是，有可能对粗大单核细胞进行基因改造，并将其用作“特洛伊木马”传递系统，将基因转移到中枢神经系统，以治疗神经艾滋病。 该项目将作为夏威夷大学和罗切斯特大学研究人员之间综合、协调的合作进行。该项目的申请人部分将重点测试和比较分析不同病毒载体转导血液单核细胞的潜在能力；还将评估载体在单核细胞穿越血脑屏障方面的努力。还将进行实验以确定（1）用有缺陷的干扰慢病毒载体（DLV）转导的单核细胞是否不太容易复制感染性HIV-1，以及（2）DLV是否可以被动员、扩增并传播给未转导的旁观者细胞受到感染性 HIV-1 的影响。该应用程序的合作者部分将重点分析载体转导的单核细胞是否释放与细胞激活相关的可溶性神经毒性因子。此外，合作者构建了编码可溶性神经保护因子的病毒载体，并将确定用该载体转导的单核细胞是否能够促进暴露于明确的候选HIV神经毒素的旁观神经元的存活。整个项目由一个紧密结合的整体组成，并将允许研究人员以最大生产力和互惠互利的方式应用互补的专业知识。此次合作还将为 PI 及其学生和研究员提供充足的机会，以获得神经科学和广泛的相关技术方面的培训。总体而言，这项工作预计将为治疗神经艾滋病和其他神经系统疾病的新方法带来重要的见解。