While blood brain barrier (BBB) impairment is a critical feature of HIV-1 neuropathogenesis, the BBB also serves as a conduit for therapeutics brain delivery. How this intersects with BBB pathophysiology is the focus of the current project. It is a now well-established fact that neural progenitor cells (NPC) dynamically contribute to neuro- and gliogenesis in the postnatal brain and are being developed in this program grant (project 1, J. Zheng). In response to injury, infection, or neurodegeneration, progenitor cells migrate toward zones of tissue damage. Chemokines produced in association with neuroinflammatory responses likely act as chemoattractants for neural progenitors during brain injury. Whether NPC cross the BBB from blood remains unclear. We propose that systemic NPC can migrate across the BBB and promote neuroprotection while attenuating neuroinflammation in HIV-1 encephalitis (HIVE). We will study mechanisms governing NPC migration and their effect on the BBB using the pathophysiologically relevant assumption of chemokine overproduction in neuroinflammation. We will investigate how migration across the BBB alters how NPC differentiate into neurons and glia and the effects of NPC on the BBB from within the brain. Strategies in this program grant are being developed that enable a broad spectrum of anti-retroviral and adjunctive medicines for HIV-1 to be packaged into nanoparticles (NP;project 2, H. Gendelman). These can be taken by leukocytes and transported into areas of active neuroinflammation. While being an attractive specific way to facilitate anti-retroviral or anti-inflammatory drug delivery, it is currently unknown how NP-containing leukocytes affect BBB function during migration or from the 'brain'side of the barrier and perhaps even more importantly how they affect neuronal and glial integrity. Therefore, we will address the pathways and nanotoxicology for migration of macrophages across BBB with drug laden NP. We will evaluate the cell's ability to move and affect the integrity and function of the BBB and to affect diseaserelated neuropathology. These cell-based novel therapeutic approaches are interdisciplinary and show ynergy amongst the projects (NPC project 1, J. Zheng and NP-delivery of drugs project 2, H. Gendelman) with our own established expertise in BBB models. Importantly, three diverse animal models for HIVE will be employed to validate in vitro observations using in vivo imaging techniques allowing assessment of BBB integrity, neuronal injury, and neuroinflammation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Medical Center
United States
Zip Code
Araínga, Mariluz; Edagwa, Benson; Mosley, R Lee et al. (2017) A mature macrophage is a principal HIV-1 cellular reservoir in humanized mice after treatment with long acting antiretroviral therapy. Retrovirology 14:17
Merkel, Steven F; Razmpour, Roshanak; Lutton, Evan M et al. (2017) Adolescent Traumatic Brain Injury Induces Chronic Mesolimbic Neuroinflammation with Concurrent Enhancement in the Rewarding Effects of Cocaine in Mice during Adulthood. J Neurotrauma 34:165-181
Gnanadhas, Divya Prakash; Dash, Prasanta K; Sillman, Brady et al. (2017) Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs. J Clin Invest 127:857-873
Shahnaz, Gul; Edagwa, Benson J; McMillan, JoEllyn et al. (2017) Development of mannose-anchored thiolated amphotericin B nanocarriers for treatment of visceral leishmaniasis. Nanomedicine (Lond) 12:99-115
Embury, Christine M; Dyavarshetty, Bhagyalaxmi; Lu, Yaman et al. (2017) Cathepsin B Improves ß-Amyloidosis and Learning and Memory in Models of Alzheimer's Disease. J Neuroimmune Pharmacol 12:340-352
Edagwa, Benson; McMillan, JoEllyn; Sillman, Brady et al. (2017) Long-acting slow effective release antiretroviral therapy. Expert Opin Drug Deliv 14:1281-1291
Guo, Dongwei; Zhou, Tian; Araínga, Mariluz et al. (2017) Creation of a Long-Acting Nanoformulated 2',3'-Dideoxy-3'-Thiacytidine. J Acquir Immune Defic Syndr 74:e75-e83
Kevadiya, Bhavesh D; Bade, Aditya N; Woldstad, Christopher et al. (2017) Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging. Acta Biomater 49:507-520
Sajja, Balasrinivasa R; Bade, Aditya N; Zhou, Biyun et al. (2016) Generation and Disease Model Relevance of a Manganese Enhanced Magnetic Resonance Imaging-Based NOD/scid-IL-2R?c(null) Mouse Brain Atlas. J Neuroimmune Pharmacol 11:133-41
Araínga, Mariluz; Su, Hang; Poluektova, Larisa Y et al. (2016) HIV-1 cellular and tissue replication patterns in infected humanized mice. Sci Rep 6:23513

Showing the most recent 10 out of 227 publications