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

• 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
• 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' 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

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联系的流行病。尽管可卡因滥用对HIV-1相关神经系统疾病的临床过程有了公认的影响，但可卡因调节中枢神经系统病理学能力的基础机制仍然难以捉摸。大脑中的HIV感染不仅会损害神经元（突触）功能和丧失，而且还会对神经发生产生负面影响，从而导致海马齿状回的成年神经祖细胞（NPC）的产生较少。可卡因还被证明会降低神经祖细胞的增殖能力，从而损害海马的自我更新能力。成年神经发生减少是导致神经辅助发病机理的关键因素之一。因此，首先，了解可卡因和HIV-1蛋白（TAT）介导的NPC损伤的基础机制，其次是开发克服这些关键细胞损伤的治疗策略。神经发生由神经营养蛋白家族通过多种信号传导机制调节。来自我们小组的初步数据已经确定了一个新的因子，血小板衍生的生长因子-B链（PDGF-B），该因子是体外和体内系统的多巴胺能神经元的神经保护剂。我们还证明了PDGF介导的中脑神经元的保护涉及瞬时受体电位规范通道（TRPC）介导的Ca2+进入。众所周知，Ca2+进入在神经元存活和NPC的扩散中都起着关键作用。因此，我们假设HIV反式激活蛋白（TAT）和可卡因介导的神经发生障碍可以通过TRPC信号的作用来逆转神经发生的损害，从而恢复NPC增殖和分化。为了解决这一假设，提出了三个具体目的：1）检查由HIV TAT和可卡因在海马NPC中介导的神经发生受损的pDGF-B调节的逆转，重点是TRPC通道，2）2）研究与PDGF-B型 - 脉冲调节的信号探测的神经启动和3） - 均应探讨的态度2）。 （AAV2）-pDGF-B作为改善可卡因介导的鼠类手动模型中神经发生的抑制作用的干预策略。这些研究既新颖又是创新的，因为PDGF-B在废除神经发生下的功效不仅对手可能具有价值，而且还适用于其他神经退行性疾病。