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Gelbard Lab

Glial and Immune Effector Cell Interactions with Synapses During Neuroinflammation

Research Overview

Neurons exposed to MLK3 inhibitors display
normal morphology and expression of MAP-2

Our lab’s interests have been shaped by trying to understand how HIV-1 can disrupt normal cognitive functions by altering homeostasis between microglia and synaptic networks.  Much like experience-driven synaptic plasticity, this has been and continues to be a work in progress influenced by our trainees’ interests, the experimental approaches they have formulated to help us understand how innate immunity can both shape and repair the central nervous system (CNS), and the novel results that they have produced.  Our laboratory has no single technique that has influenced our approach to understanding how the virus can disrupt normal synaptic transmission, although we favor methods that allow us to visualize our data, preferably in real time. Because my training as a molecular neuropharmacologist has emphasized understanding how signaling pathways can be disrupted during disease and whether these pathways can be restored to a new homeostatic relationship between the immune system and vulnerable synaptic networks, we have focused on kinase signaling that controls neuroinflammation.  Our efforts to both understand how HIV-1 infection in the CNS disrupts this type of kinase signaling and create small molecule inhibitors of the mixed lineage kinases (MLKs) so that we could test this as a therapeutic approach to HIV-1 associated neurocognitive disorders (HAND), led us to the current point of successfully developing a new class of drugs that inhibit MLKs in macrophages/microglia and neurons to restore homeostasis.  This has been extraordinarily serendipitous for us, because we have realized that loss of homeostasis between an end organ target cell, whether it is a neuron, cardiomyocyte or hepatocyte can be restored, with disease-modifying outcomes in HAND, MS (using an EAE model employed by Dr. Matt Bellizzi in our lab), post-operative cognitive dysfunction (POCD; in collaboration with Dr. Niccolo Terrando at Duke University), Alzheimer’s disease (with Dr. Gendelman at UNMC and Drs. Todd Krauss and Brad Nilsson at UR), non-alcoholic steatohepatitis (NASH; in collaboration with Dr. Samar Ibrahim at Mayo Clinic) and ischemia-reperfusion injuries (MI; in collaboration with Dr. Burns Blaxall at the Cincinnati Children’s Hospital).  Lastly, and perhaps most importantly to our lab’s core mission, in work we have done with Dr. Howard Gendelman (UNMC) and Drs. Maggirwar and Dewhurst here at URMC, we have discovered that the combination of nanoformulated antiretroviral therapy (nanoART, developed by Dr. Gendelman) for HIV-1 and our lead compound for inhibition of MLKs, URMC-099, can reverse HIV-1 blockade of autophagy in persistently infected macrophages, allowing nanoART to effectively eliminate HIV-1 without inflammation and bystander cellular damage.  This has led to additional approaches to new therapies both for HAND and eradication of persistent HIV-1 infection.

For trainees at the pre- and postdoctoral level, we are currently investigating the role of the transcription factor, Mafb, using a combination of optogenetic and CRISPR/Cas9 techniques, in regulating a neuroinflammatory response during HIV-1 infection of the CNS; the role of soluble intercellular adhesion molecule type 5 (sICAM-5) as a biomarker for synaptodendritic damage during HAND; dysregulation of complement signaling during HAND and MS; and therapeutic strategies to repair hippocampal and cortical synaptic injury during MS that remain resistant to current immunomodulatory therapies.  Additional projects related to our collaborations with other investigators described above are also ongoing.

Publications

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Contact Us

  Gelbard Lab
601 Elmwood Ave
Rochester, NY 14642

 Susan A. Brightman, Administrator
(585) 273-1473
Susan_Brightman@urmc.rochester.edu

 Harris Gelbard, Principal Investigator
(585) 273-1473
harris_gelbard@urmc.rochester.edu

 Angela Stout, Lab Manager
(585) 275-7391
Angela_Stout@urmc.rochester.edu