PDGF-BB Reverses Impaired Neurogenesis Mediated by Tat and Cocaine

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. PUBLIC HEALTH RELEVANCE: Cocaine, a highly potent and addictive brain stimulant, often abused by HIV-infected patients, is known to exacerbate HIV-associated CNS disease while reducing the proliferative and differentiation capacity of the stem cell pool. This proposal is aimed at understanding molecular mechanisms by which a novel target PDGF- B chain, reverses the combined deleterious effects of HIV-1 protein Tat and cocaine on neural progenitor stem cells both in cell culture and in the whole animals.