Welcome to the Gelbard Lab
Glial and Immune Effector Cell Interactions with Synapses During Neuroinflammation
Human immunodeficiency virus type 1 (HIV-1) remains a healthcare challenge after 30 years of efforts to eradicate it. Despite the fact that combination antiretroviral therapy (cART) has made AIDS a chronic, treatable disease, it has proven considerably less effective as a therapy for HIV-1 associated neurocognitive disorders (HANDs), despite its ability to drive viral load to undetectable levels. With over one million people infected with HIV-1 in the U.S. and well over 35,000,000 people infected worldwide, HIV-1's ability to enter the CNS early in the course of infection, makes it a major source of neurologic morbidity, especially in a population that is aging and beginning to experience other neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Because HIV-1 infects cells of mononuclear lineage, but not post-mitotic neurons, it disrupts normal CNS functions by the production and secretion of pro-inflammatory cellular metabolites and viral gene products that act as neurotoxicants. Our laboratory has investigated the effects of these neurotoxins on normal immune effector functions in the CNS as well as synaptic function. Our working conclusion is that initial infection with the virus in the CNS leads to a change in the functional phenotype of immune effector cells, leading to chronic neuroinflammation and failure of synaptic communication.
In particular, we have focused on how HIV-1 neurotoxins disrupt the normal function(s) of two enzyme targets, glycogen synthase kinase 3 beta (GSK-3b) in neurons, and mixed lineage kinase 3 (MLK3) in neurons and perivascular macrophage/microglia, with the ultimate goal of designing small molecule therapies to prevent their pathologic over-activation by inflammatory neurotoxins. As part of this collaborative effort between several labs at our institution, we have utilized novel optical imaging techniques to better understand nano-scale changes that occur to synaptic architecture during inflammation, as well as gain insight into how cells with immune effector functions can directly effect synaptic transmission. We do this with the goal of determining what the bioenergetic consequences of synapse remodeling are in the face of immune activation, and whether inflammation inevitably leads to loss of functional synaptic architecture with the ability to retain plasticity. Ultimately, we believe that loss of homeostasis between synapses and immune effector cells may be common phenomena to many neurodegenerative diseases with an inflammatory component.
Showing 2 of 103 journal articles.
Polesskaya O; Wong C; Lebron L; Chamberlain JM; Gelbard HA; Goodfellow V; Kim M; Daiss JL; Dewhurst S. "MLK3 regulates fMLP-stimulated neutrophil motility." Molecular immunology.. 2014; 58(2):214-22. Epub 2014 Jan 03.
Kapetanovic S; Griner R; Zeldow B; Nichols S; Leister E; Gelbard HA; Miller TL; Hazra R; Mendez AJ; Malee K; Kammerer B; Williams PL; . "Biomarkers and neurodevelopment in perinatally HIV-infected or exposed youth: a structural equation model analysis." AIDS.. 2014; 28(3):355-64.