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, Neurological Sciences, 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.
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.
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.
Prodrug Formulations Create Sustained Release Antiretrovirals
MPI: Gendelman, H.E./Edagwa, B.
NIH/NIA 1 R01AI145542
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.
Glutaminase and its neurotoxic link to HAND
PI: Gendelman, H.E.
NIH/NINDS R01 NS097195
This grant is to investigate the role of glutaminase in the pathogenesis of HAND and it associated pathways. The role of MV in mediating brain inflammation are also investigated.
HIV Theranostics
PI: Gendelman, H.E.
NIH/NIMH R01MH121402
This award is to convert nucleoside reverse transcriptase and an integrase inhibitor(s) into long-acting slow effective release antiretroviral nanocrystals with improved safety and efficacy against human immunodeficiency virus infection. Prodrug nanocrystals are lipophilic and stabilized by biocompatible surfactants. The formulations are being developed with the potential to extend drug-dosing intervals up to once every six months.
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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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 |
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Tanmay Kulkarni Graduate Research Assistant Pharmaceutical Sciences |
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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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Insiya Mukadam Graduate Research Assistant Pharmaceutical Sciences |
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| Krista Namminga Research Technician II |
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Kate Olson-Johnson, Ph.D. |
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Lana Reichardt |
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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 Research Technologist, II |
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Nathan Smith, Ph.D. |
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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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| Melinda Wojtkiewicz Research Project Specialist |
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