Research Goals
Collaborators
Funding
Techniques used in the lab
Personnel
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Research Goals
The long-range goals of the laboratory are to develop immunopharmacological approaches to improve the diagnosis and treatment options for neurodegenerative diseases that include HIV-1 associated neurocognitive disorders (HAND) and Parkinson's disease (PD).
The laboratory initiative is divided into specific programs, each co-headed by an experienced scientist. Specific expertise in immunology, molecular biology, infectious disease, proteomics, physiology and pathogenesis is provided to the student and research fellow.
First, studies revolving around the development of nanoformulated cell-based drug delivery with a special focus on the CNS. Nanotoxicology studies involve the studies of the regulation of leukocyte entry into peripheral and neural tissues with a focus on glial immunity. This is seen during neurodegenerative diseases and include studies of HAND and PD. Those that are being developed include, but are not limited to, antiretroviral, neuroprotective, and anti-inflammatory drugs.
Second, drug testing (neuroprotective and neuroregenerative) and improved diagnostics for HAND are being developed in virus-infected immunodeficient mice. This program is part of national grant efforts that involve scientists at the University of Nebraska Medical Center, the University of Rochester and Columbia University College of Physicians and Surgeons. The focus is to perform translational research that would move quickly from animals to humans.
Third, proteomic and metabolomic approaches for biomarker discovery are linked to studies of cell-cell interactions for disease. This is part of a broader initiative of how drugs of abuse influence viral replication and immune dysregulation.
Fourth, neuroimmunologic and vaccine approaches that induce protective immunity and neuroregeneration are being pursued in animal models of HAND, PD and amyotrophic lateral sclerosis. The laboratory has developed a unique immunization approach that uses the immune system as a cell source for brain repair during neurodegeneration.
Collaborators
Yazen Alnouti, Pharmaceutical Science, UNMC, Omaha, NE
Tatiana Bronich, Center for Drug Delivery and NanoMedicine, Department of Pharmaceutical Sciences
Benson Edagwa, Pharmacology and Experimental Neuroscience, UNMC, Omaha, NE
Howard S. Fox, Pharmacology and Experimental Neuroscience, UNMC, Omaha, NE
Harris A. Gelbard, University of Rochester School of Medicine, Rochester, NY
Santhi Gorantla, Pharmacology and Experimental Neuroscience, UNMC, Omaha, NE
Yutong Liu, Radiology, UNMC, Omaha, NE
Surya Mallapragada, Iowa State University, Ames, IA
JoEllyn McMillan, Pharmacology and Experimental Neuroscience, UNMC Omaha, NE
R. Lee Mosley, Pharmacology and Experimental Neuroscience, UNMC, Omaha, NE
Balaji Narasimhan, Iowa State University, Ames, IA
Larisa Poluektova, Pharmacology and Experimental Neuroscience, UNMC, Omaha, NE
Scott Shandler, Longevity Biotech, Philadelphia, PA
David Volsky, Icahn School of Medicine at Mount Sinai, New York, NY
Charles Wood, Nebraska Center for Virology, UNL, Lincoln, NE
Funding
NanoART Manufacture, Delivery and Pharmacokinetics for Optimizing Drug Adherence
PI: Gendelman, H. E.
NIH/NIDA P01 DA028555
This is an integrative cross approach translational and multi-investigator program grant seeking to develop nanoformulated antiretroviral drug therapy from the bench to the patient.
Neuroprotective Immunity and HIV Dementia
PI: Gendelman, H. E.
NIH/NINDS NS034239
This proposal will determine cell responses in macrophages following HIV-1 infection and engagement with T cells and T cell subsets. Macrophage functions including phagocytosis, antigen presentation, intracellular killing and effector cell responses and their modulation by T cells is a focus for this work. Signal transduction pathways and mechanisms for virus-induced neurotoxicity or neuroprotection will be developed.
Nanomedicine and NeuroAIDS
PI: Gendelman, H. E.
NIH/NINDS R01 NS036126
This research proposes to investigate the biophysiological properties of monocytes and monocyte-derived macrophages that influence cell migration both across the blood-brain barrier and within the brain. The central hypothesis is that changes in ion channel expression in monocytes and macrophages following exposure to virus and immune products influences the cell's ability to change its volume and shape, thus influencing cell migration. Such events are pivotal for macrophages to enter the brain and to secrete the toxins that underlie the neuropathogenesis of HIV-1 associated dementia.
Neuroimmunology of Disease Training Program
MPI: Gendelman, H.E. and Monaghan, D.
NIH/NINDS T32 NS105594
This program will provide unique research training experiences in infectious, developmental, and degenerative nervous system diseases. By combining cross-disciplinary team-mentored training in the immune-brain axis, the next generation of neuroscientists will be able to incorporate multidisciplinary approaches into novel research paradigms. This is done to better understand disease processes and develop state-of-the-art diagnostic and therapeutic interventions. The University of Nebraska Medical Center is well positioned to offer this unique cross-disciplinary educational experience.
Chronic HIV infection and Aging in NeuroAIDS (CHAIN) Center
MPI: Buch, S and Fox, H.; Therapeutics Core Leader: Gendelman, H. E.
NIH/NIMH P30 MH062261
This is a Center grant to provide Administrative and Core Support for scientists investigating NeuroAIDS.
Combined Molecular Excision Therapy (CMET) for Eliminating HIV-1
PI: Gendelman, H.E.
NIH/NIMH R01MH115860-01
In this proposal we seek to eradicate the human immunodeficiency virus (HIV) from its central nervous system and peripheral reservoirs. Dual humanized brain and immune system mice were created to reflect the complex neuroimmune communication networks seen in human disease. These mice will be used to assess brain viral reservoirs during combination antiretroviral therapy (cART) and gene delivery of a CRISPR/Cas9 for final viral excision. HIV elimination will be determined after cessation of cART and elimination of viral rebound.
CNS Reservoirs of HIV in a Mouse Model of HIV Infection and Cognitive Impairment
PI: Gendelman, H.E.
Icahn School of Medicine at Mount Sinai
This proposal is designed to develop a number of novel anti-retroviral clearance mechanisms to best reduce or perhaps eradicate virus within its brain reservoir. The use of highly active antiretroviral drugs are designed to restrict viral growth as maximally possible and as such best enable viral clearance by immune potentiating and eliminating agents develop by investigators at Mount Sinai Hospital and Medical Center.
Cell Targeted long-acting nanoformulated antiretroviral therapy- (Research Collaboration Agreement-UNeMed)
PI: Gendelman, H.E.
ViiV Healthcare Limited
These studies aim to develop formulation platforms for a long-acting integrase, a CCR5 inhibitor and a nucleoside reverse transcriptase inhibitor for once monthly therapies with reduced injection volumes and viral reservoir targeting.
Chemical, Nanomedicine and Autophagy Strategies to Create Sustained-Release Antiretrovirals
PI: Gendelman, H.E.
NIH/NIA 1 R56 AI138613
This award will be used to convert short acting antiretroviral drugs into long-acting slow effective release ART (LASER ART) with potent and selective activities against the human immunodeficiency virus type one (HIV-1). The LASER ART chemically modified to create hydrophobic and lipophilic drug crystals in order to extend the drug dosing intervals from once/day to once/6 months. The generation of decorated drug nanocrystals can be boosted by a second medicine that protects the first from cell destruction and thereby serves to improve reservoir delivery to body tissue sites where HIV-1 grows such as the lymph nodes and gut
Long Acting GM-CSF for Parkinson's Disease
PI: Gendelman, H.E.
UNeMed
This proposal is broken into 4 phases. In phase one, we will compare 2 long-acting GM-CSF (laGM-CSF) molecules (huSYNAGIS_muGMCSF and huHERCEPTIN_muGMCSF) to recombinant mouse GM-CSF (rmGM-CSF) in C57BL/6J male mice, 8 weeks of age. In phase two, we will test neuroprotective capacity of the 1 lead laGM-CSF molecule in acute models of Parkinsonian neurodegeneration. In phase 3, we will start In vitro studies for Treg induction, Treg expansion, duration of in vitro effect will be performed from human cell isolates and phase. And lastly in stage 4, we will test neuroprotective capacity in chronic mouse model of Parkinsonian neurodegeneration.
Novel Kinase and Nanoformulated Protease Inhibitors for Eradication of CNS HIV-1
PI: Gendelman, H.E.
University of Rochester
This proposal is designed to develop a means to eradicate viral infection from its CNS reservoir. The overarching idea is to facilitate crystalline nano formulated antiretroviral drug entry into monocyte-macrophage within late and recycling endosomes by affecting/harnessing phagolysosomal fusion events through the new kinase inhibitor URMC-099. The research is divided equally amongst University of Nebraska and University of Rochester scientists experienced in virology, immunology, pharmacology and neuroscience to pool resources towards a functional HIV-1 cure.
Parkinson's Technology
PI: Gendelman, H.E.
Moderna Therapeutics
Improve the delivery of an immune transformative agent by engagement of a liposomal delivery system for RNA rather than protein in the treatment of Parkinson's disease.
Techniques used in laboratory
- Chimeric Mice
- Fluorescent microscopy
- HIV-1 neurotoxicity assay
- Immunohistochemistry
- Macrophage migration tracking
- Mouse intracerebral stereotactic inoculation
- Mouse models of HIV-1 encephalitis
- Nano-medicine macrophage delivery
- Pathology analysis
- Primary brain and immune cell culture
- Real-time PCR
- Small animal model drug therapy
- Western blotting
- iTRAC and SWATH proteomics
- Flow cytometry/FACS
Personnel
| Aditya Bade, Ph.D. Instructor |
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Mary Banoub Graduate Research Assistant |
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| Denise Cobb Graduate Research Assistant |
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Prasanta Dash, Ph.D. Instructor |
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| Benson Edagwa, Ph.D. Assistant Professor |
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Liyang Guo Other Hourly Worker |
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| Mahmudul Hasan Graduate Research Assistant Pharmaceutical Sciences |
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Jonathan Herskovitz Graduate Research Assistant Immunology, Pathology, & Infectious Disease |
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James Hilaire |
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| Tanmay Kulkarni Graduate Research Assistant Pharmaceutical Sciences |
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Zhiyi Lin, Ph.D. Post-Doc Research Associate |
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Yaman Lu |
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Jatinhumar Pravi Machhi |
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JoEllyn McMillan, Ph.D. |
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Marwa Mohamed |
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| Insiya Mukadam Graduate Research Assistant Pharmaceutical Sciences |
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Krista Namminga |
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| Maxim Oleynikov Student Scholar |
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Kate Olson-Johnson, Ph.D. Post-Doc Research Associate |
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Brendan Ottemann |
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Lana Reichardt Administrative Associate |
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| Aaron Schwab Research Technologist |
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Brady Sillman, Ph.D. Post-Doc Research Associate |
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Bhagya Laxmi Dyavar Shetty |
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Dhruvkumar Soni |
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| Sruthi Sravanam Research Technologist |
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Hang Su Graduate Research Assistant |
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| Mackenzie Thurston Graduate Assistant-Research Intern |
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Melinda Wojtkiewicz Research Project Specialist |
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