PDGF-BB Reverses Impaired Neurogenesis Mediated by Tat and Cocaine

描述(由申请人提供)： 艾滋病毒-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相关神经疾病的临床过程产生了公认的影响，但可卡因调节中枢神经系统病理的潜在机制仍然不清楚。大脑中的HIV感染不仅会损害神经元(突触)的功能和丧失，而且还会对神经发生产生负面影响，导致海马齿状回中生成的成年神经前体细胞(NPC)减少。可卡因还被证明降低了神经前体细胞的增殖能力，从而削弱了海马体的自我更新能力。成人神经发生减少是神经艾滋病发病的关键因素之一。因此，必须首先了解可卡因和HIV-1蛋白(TAT)介导的神经前体细胞损伤的潜在机制，其次，制定克服这些关键细胞池损伤的治疗策略。神经发生是由一系列神经营养因子通过广泛的信号机制来调节的。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都可以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规范通道(TRPC)介导的钙内流。已知钙离子内流在神经元存活和神经前体细胞的增殖中都起着关键作用。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损伤可以被PDGF-B通过TRPC信号的作用逆转，恢复鼻咽癌的增殖和分化。针对这一假说，提出了三个具体的目标：1)检测PDGF-B对HIV、TAT和可卡因介导的受损神经发生的逆转作用，重点是TRPC通道；2)研究PDGF-B介导的神经发生调控的信号通路；3)在Hand小鼠模型中，测试腺相关病毒2(AAV2)-PDGF-B作为改善TAT和可卡因介导的神经发生抑制的干预策略的治疗潜力。这些研究都是新颖和创新的，因为PDGF-B在消除神经再生减少方面的疗效不仅对手部有价值，而且也适用于其他神经退行性疾病。

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.