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: 8591388
• 负责人: Shilpa J. Buch
• 金额: $ 33.41万
• 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/8591388
• 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; Platelet-Derived Growth Factor Receptor; 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关联的流行病。尽管可卡因滥用对HIV-1相关神经系统疾病的临床过程的影响是公认的，但可卡因调节中枢神经系统病理学能力的机制仍然难以捉摸。脑中的HIV感染不仅可以损害神经元（突触）功能和损失，而且还可以负面地影响神经发生，导致在海马的齿状回中产生更少的成年神经祖细胞（NPC）。此外，还发现海马体可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。成体神经发生减少是导致NeuroAIDS发病的关键因素之一。因此，重要的是，首先，了解可卡因和HIV-1蛋白（达特）介导的损害NPC的机制，其次，开发治疗策略，克服这些关键池的细胞的损害。神经发生由神经营养因子家族通过广泛的信号传导机制调节。我们小组的初步数据已经确定了一种新的因子，血小板衍生生长因子-B链（PDGF-B），在体外和体内系统中作为多巴胺能神经元的神经保护剂。我们还证明了PDGF介导的中脑神经元保护涉及瞬时受体电位典型通道（TRPC）介导的Ca 2+进入。已知Ca 2+内流在神经元存活和NPC增殖中起关键作用。因此，我们推测，HIV反式激活蛋白（达特）和可卡因介导的神经发生损伤可以被PDGF-B逆转，通过TRPC信号的作用，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PDGF-B调节的海马NPC中由HIV达特和可卡因介导的受损神经发生的逆转，重点是TRPC通道，2）研究参与PDGF-B介导的神经发生调节的信号通路，和3）测试腺相关病毒2（AAV 2）-PDGF-B作为改善达特和可卡因-可卡因代谢的干预策略的治疗潜力。介导的HAND小鼠模型中神经发生的抑制。这些研究是新颖的和创新的，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。