PDGF-BB Reverses Impaired Neurogenesis Mediated by Tat and Cocaine

PDGF-BB 逆转 Tat 和可卡因介导的受损神经发生

基本信息

批准号：
8410574
负责人：
Shilpa J. Buch
金额：
$ 32.08万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-15 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8410574
关键词：
AIDS neuropathy Address Adult Affect Alzheimer&apos s Disease Animals Astrocytes Binding Brain Brain Pathology Brain-Derived Neurotrophic Factor Bromodeoxyuridine CREB1 gene Calcium Cell Culture Techniques Cell Proliferation Cells Central Nervous System Diseases Clinical Cocaine Cocaine Abuse Coupled Data Dementia Dependovirus Down-Regulation Drug abuse Epidemic Exhibits Family Fibroblast Growth Factor Generations Genetic Glial Fibrillary Acidic Protein Goals HIV HIV Infections HIV Seropositivity HIV-1 Hippocampus (Brain)Human Impaired cognition Impairment In Vitro Incidence Individual Infection Intervention Learning Life Link Macaca Mediating Memory Midbrain structure Modeling Molecular Monitor Multiple Sclerosis Mus Needle Sharing Neuraxis Neurodegenerative Disorders Neurons Neuroprotective Agents Parahippocampal Gyrus Parkinson Disease Pathogenesis Pathology Pathway interactions Patients Pharmaceutical Preparations Phospholipase C Platelet-Derived Growth Factor Play Prevalence Protein Overexpression Proteins Proto-Oncogene Proteins c-sis Rattus Recombinant adeno-associated virus (rAAV)Regulation Reporting Rodent Model Role SIV Signal Pathway Signal Transduction Small Interfering RNA Staining method Stains Stem cells Survival Rate System Testing Therapeutic adult neurogenesis antiretroviral therapy cocaine exposure dentate gyrus dopaminergic neuron drug of abuse efficacy testing global health human embryonic stem cell in vivo indexing inhibitor/antagonist innovation intravenous drug use migration nerve stem cell nervous system disorder neurogenesis neuron apoptosis neuronal survival neurotrophic factor non-drug novel platelet-derived growth factor BB receptor relating to nervous system self-renewal stem synaptic function therapeutic development transmission process

项目摘要

DESCRIPTION (provided by applicant): HIV-1 infection and drug abuse are interlinked epidemics. Despite the recognized impact of cocaine abuse on the clinical course of HIV-1-associated neurological disorder, the mechanisms underlying the ability of cocaine to modulate central nervous system pathology remain elusive. HIV-infection in the brain can not only impair neuronal (synaptic) function and loss, but can also negatively impact neurogenesis resulting in generation of fewer adult neural progenitor cells (NPCs) in the dentate gyrus of the hippocampus. Cocaine has also been shown to decrease the proliferative capacity of neural progenitors thus impairing the self-renewal ability of the hippocampus. Diminished adult neurogenesis is one of the key factors contributing to pathogenesis of NeuroAIDS. It is therefore essential to first, understand the mechanisms underlying cocaine and HIV-1 protein (Tat)-mediated impairment of NPCs and secondly, to develop therapeutic strategies that overcome the impairment of these key pool of cells. Neurogenesis is regulated by a family of neurotrophins via a wide range of signaling mechanisms. Preliminary data from our group have identified a novel factor, platelet-derived growth factor-B chain (PDGF-B) that acts as a neuroprotective agent for dopaminergic neurons both in vitro and in vivo systems. We have also demonstrated that PDGF-mediated protection of midbrain neurons involves transient receptor potential canonical channels (TRPC)-mediated entry of Ca2+. Ca2+ entry is known to play a critical role both in neuronal survival and in the proliferation of NPCs. We therefore hypothesized that HIV transactivating protein (Tat) & cocaine-mediated impairment of neurogenesis can be reversed by PDGF-B, through the action of TRPC signaling, to restore NPC proliferation and differentiation. To address this hypothesis three specific aims are proposed: 1) Examine PDGF-B-regulated reversal of impaired neurogenesis mediated by HIV Tat & cocaine in hippocampal NPCs with emphasis on TRPC channels, 2) Investigate the signaling pathways involved in PDGF-B-mediated regulation of neurogenesis, and 3) Test the therapeutic potential of Adeno-associated virus 2 (AAV2)-PDGF-B as an intervention strategy for ameliorating Tat & cocaine-mediated inhibition of neurogenesis in murine models of HAND. These studies are both novel and innovative in that the efficacy of PDGF-B in abrogating decreased neurogenesis can be of value not only for HAND but can be applicable to other neurodegenerative diseases as well.

描述（由申请人提供）： HIV-1 感染和药物滥用是相互关联的流行病。尽管人们已经认识到可卡因滥用对 HIV-1 相关神经系统疾病的临床病程有影响，但可卡因调节中枢神经系统病理能力的机制仍然难以捉摸。大脑中的 HIV 感染不仅会损害神经元（突触）功能和丧失，还会对神经发生产生负面影响，导致海马齿状回中成体神经祖细胞 (NPC) 的生成减少。可卡因还被证明会降低神经祖细胞的增殖能力，从而损害海马体的自我更新能力。成人神经发生减少是导致 NeuroAIDS 发病的关键因素之一。因此，有必要首先了解可卡因和 HIV-1 蛋白 (Tat) 介导的 NPC 损伤的机制，其次制定克服这些关键细胞池损伤的治疗策略。神经发生由神经营养素家族通过多种信号传导机制调节。我们小组的初步数据已经确定了一种新的因子，即血小板衍生生长因子-B 链 (PDGF-B)，它在体外和体内系统中均可作为多巴胺能神经元的神经保护剂。我们还证明，PDGF 介导的中脑神经元保护涉及瞬时受体电位经典通道 (TRPC) 介导的 Ca2+ 进入。已知 Ca2+ 进入在神经元存活和 NPC 增殖中发挥着关键作用。因此，我们假设 PDGF-B 可以通过 TRPC 信号传导的作用来逆转 HIV 反式激活蛋白 (Tat) 和可卡因介导的神经发生损伤，从而恢复 NPC 的增殖和分化。为了解决这一假设，提出了三个具体目标：1）检查海马 NPC 中 HIV Tat 和可卡因介导的受损神经发生的 PDGF-B 调节逆转，重点是 TRPC 通道，2）研究 PDGF-B 介导的信号通路神经发生的调节，以及 3) 测试腺相关病毒 2 (AAV2)-PDGF-B 作为改善 Tat & 的干预策略的治疗潜力可卡因介导的 HAND 小鼠模型神经发生抑制。这些研究既新颖又创新，因为 PDGF-B 在消除神经发生减少方面的功效不仅对 HAND 有价值，而且也适用于其他神经退行性疾病。