PDGF-CC Mediated Reversal of Synaptodendritic Injury in HAND

Project: Research projectResearch Project

Description

? DESCRIPTION (provided by applicant): The control and eradication of neurological complications associated with AIDS continues to be an important goal in efforts toward improving the well-being of HIV-infected patients. The overarching goal of this new application is to explore the role of platelet-derived growth factor (PDGF)-CC in reversing synaptodendritic injury & the associated cognitive decline, both of which comprise the hallmark features of HIV-associated neurocognitive disorders (HAND). Clinically, HAND is associated with reduced quality of life, memory loss, and social & occupational disabilities. Pathologically, patients with
HAND exhibit protracted forms of HIV- encephalitis (HIVE) often manifesting as subtle cognitive alterations rather than overt dementia. These patients often display neurodegenerative pathology with the involvement of cortical and subcortical regions and simplification of the synaptodendritic structure of neuronal populations in the neocortex. More importantly, reversible synaptodendritic neuronal injury is emerging as an important phenotype of HAND. Preliminary data from our lab has identified a novel factor - PDGF-C that acts as a neuroprotective agent both in vitro for dopaminergic neurons exposed to HIV proteins Tat & gp120 and, in vivo in rodent models of HAND. Furthermore, we have also demonstrated that down-regulation of this factor correlated with increased neuronal dysfunction in the brains of SIV-infected macaques/HIV-infected humans with encephalitis. We have also demonstrated that exposure to HIV Tat & gp120 resulted in loss of spines in hippocampal neurons both in cell culture as well as in vivo in a rodent model administered viral protein in the hippocampus. Intriguingly, Tat- induced spine loss was reversed by pre-exposure of neurons to PDGF-CC. Based on these findings the underlying central hypothesis of this proposal is that loss of dendritic spines & functional synapses (synaptodendritic) and the associated cognitive decline mediated by HIV proteins can be reversed by PDGF- CC, through activation of intracellular signaling pathways. The proposed hypothesis will be tested in 3 specific aims: 1) To determine the expression of synaptic damage & PDGF-CC and correlate it with glial activation in the brains of humans with HAND and in macaques with SIV-infection and ART therapy; 2) To determine the molecular mechanisms involved in PDGF-CC mediated reversal of HIV Tat/gp120-induced dendritic spine and synaptic loss & 3) To determine the neuroprotective efficacy of lentivirus (LV)-PDGF-C administered intrahippocampally in the humanized model of HAND. These studies are both novel and innovative in that the efficacy of PDGF-CC in restoring synaptic plasticity can have implications not only for HAND but also for other neurodegenerative diseases.
StatusActive
Effective start/end date7/3/155/31/20

Funding

  • National Institutes of Health: $453,202.00
  • National Institutes of Health: $477,659.00

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Platelet-Derived Growth Factor
HIV
Wounds and Injuries
Dendritic Spines
Macaca
Encephalitis
Rodentia
Spine
Neurocognitive Disorders
Human Immunodeficiency Virus tat Gene Products
HIV Envelope Protein gp120
Human Immunodeficiency Virus Proteins
Neurons
Lentivirus
Neuronal Plasticity
Dopaminergic Neurons
Neocortex
Memory Disorders
Brain
Neuroprotective Agents

Keywords

  • Medicine(all)