PDGF-BB REVERSES IMPAIRED NEUROGENESIS MEDIATED BY TAT AND COCAINE
Yao Honghong
University Of Nebraska Medical Centercity: Omaha country: United States (us)
Grant 1R01DA033150-01 from National Institute On Drug Abuse
Abstract: 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. 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
Keywords: Address; Adult; adult neurogenesis; Affect; AIDS neuropathy; Alzheimer`s Disease; Animals; antiretroviral therapy; Astrocytes; Binding (Molecular Function); Brain; Brain Pathology; Brain-Derived Neurotrophic Factor; Bromodeoxyuridine; Calcium; Cell Culture Techniques; Cell Proliferation; Cells; Central Nervous System Diseases; Clinical; Cocaine; Cocaine Abuse; cocaine exposure; Coupled; CREB1 gene; Data; Dementia; dentate gyrus; Dependovirus; dopaminergic neuron; Down-Regulation; Drug abuse; drug of abuse; efficacy testing; Epidemic; Exhibits; Family; Fibroblast Growth Factor; Generations; Genetic; Glial Fibrillary Acidic Protein; global health; Goals; Hippocampus (Brain); HIV; HIV Infections; HIV Seropositivity; HIV-1; Human; human embryonic stem cell; Impaired cognition; Impairment; In Vitro; in vivo; Incidence; indexing; Individual; Infection; inhibitor/antagonist; innovation; Intervention; intravenous drug use; Learning; Life; Link; Macaca; Mediating; Memory; Midbrain structure; migration; Modeling; Molecular; Monitor; Multiple Sclerosis; Mus; Needle Sharing; nerve stem cell; nervous system disorder; Neuraxis; Neurodegenerative Disorders; neurogenesis; neuron apoptosis; neuronal survival; Neurons; Neuroprotective Agents; neurotrophic factor; non-drug; novel; Parahippocampal Gyrus; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phospholipase C; Platelet-Derived Growth Factor; platelet-derived growth factor BB; Play; Prevalence; Protein Overexpression; Proteins; Proto-Oncogene Proteins c-sis; Rattus; receptor; Recombinant adeno-associated virus (rAAV); Regulation; relating to nervous system; Reporting; Rodent Model; Role; self-renewal; Signal Pathway; Signal Transduction; SIV; Small Interfering RNA; Staining method; Stains; stem; Stem cells; Survival Rate; synaptic function; System; Testing; Therapeutic; therapeutic development; transmission process
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
Project start date: 2012-01-15
Project end date: 2016-12-31
Budget start date: 15-JAN-2012
Budget end date: 31-DEC-2012
1R01DA033150-01 (2012): $334125
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Yao Honghong
COCAINE-MEDIATED NEUROINFLAMMATION: ROLE IN NEUROAIDS
Yao Honghong, Instructor
University Of Nebraska Medical Centercity: Omaha country: United States (us)
Grant 5R21DA030285-02 from National Institute On Drug Abuse
Abstract: It is becoming increasingly clear that HIV-1 infection and drug abuse are interlinked epidemics. In fact, cocaine, often abused by HIV-infected patients, has been suggested to hasten as well as worsen disease pathogenesis. HIV-1-associated neurological disorders (HAND) are primarily a result of increased influx of activated/infected monocytes from the periphery, in response to a chemokine gradient in the CNS. Among the known chemokines involved in this process, MCP-1 is known to correlate positively with HAND. Intriguingly, in our preliminary studies we have identified this chemokine as a key mediator that is up-regulated in both microglial cell line (BV-2) and in rat primary microglia that are exposed to cocaine. This effect is mediated through the cognate receptor for cocaine, the sigma receptor. We therefore hypothesized that cocaine-mediated enhancement of vascular changes in the CNS was involved in activation of sigma receptor leading to induction of MCP-1. To address this hypothesis two specific aims are proposed 1) Investigate the molecular mechanisms involved in regulation of MCP-1 in microglia exposed to cocaine and, 2) Test the therapeutic potential of sigma receptor antagonist as an intervention strategy in vivo using the HIV Tat transgenic model of HIV neurodegeneration exposed to cocaine. These studies are both novel and innovative in that the efficacy of sigma receptor in abrogating monocyte migration can be of value not only for HAND but can be applicable to other neurodegenerative diseases as well. HIV-1infected individuals that abuse cocaine have increased risk of vascular changes that can result in complications of the CNS. This study proposes to explore how cocaine abuse can lead to increased neuroinflammation, and subsequently, to develop therapeutic intervention to inhibit inflammation
Keywords: Accounting; Acquired Immunodeficiency Syndrome; Address; AIDS Dementia Complex; AIDS neuropathy; American; antiretroviral therapy; base; Binding (Molecular Function); Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Case Study; CCL2 gene; Cell Line; Cells; Central Nervous System Diseases; chemokine; Cocaine; Cocaine Abuse; cocaine exposure; cocaine receptor; Complex; Dementia; Development; Disease; Disease Progression; Drug abuse; Drug abuser; Drug usage; efficacy testing; Electrical Resistance; Endothelial Cells; Epidemic; Exhibits; global health; HIV; HIV encephalitis; HIV Infections; HIV-1; Homeostasis; Human; in vitro Model; in vivo; Incidence; Individual; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory Response; Injection of therapeutic agent; innovation; Intervention; intravenous drug use; Lead; Leukocytes; Link; Macaca; macrophage; Maintenance; Mediating; Mediator of activation protein; Microglia; migration; Molecular; monocyte; Monocyte Chemoattractant Protein-1; Mus; Needle Sharing; Nerve Degeneration; nervous system disorder; Neurodegenerative Disorders; Neuroglia; neuroinflammation; Neurons; Neuropathogenesis; neuropathology; novel; Organ; pathogen; Pathogenesis; Pathway interactions; Patients; Permeability; Play; Prevalence; prevent; Process; Property; public health relevance; Rattus; receptor; Regulation; Relative (related person); Reporting; response; Risk; Role; Route; sigma Receptors; Signal Pathway; SIV; SIV encephalitis; Source; Staging; Survival Rate; Testing; Therapeutic; Therapeutic Intervention; Tight Junctions; Transgenic Model; transmission process; Up-Regulation (Physiology); Viral Load result; Virus; Virus Replication
Relevance: HIV-1infected individuals that abuse cocaine have increased risk of vascular changes that can result in complications of the CNS. This study proposes to explore how cocaine abuse can lead to increased neuroinflammation, and subsequently, to develop therapeutic intervention to inhibit inflammation
Project start date: 2010-07-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-09-164
5R21DA030285-02 (2011): $216068