While blood brain barrier (BBB) impairment is a critical feature of HIV-1 neuropathogenesis, the BBB alsoserves as a conduit for therapeutics brain delivery. How this intersects with BBB pathophysiology is the focusof the current project. It is a now well-established fact that neural progenitor cells (NPC) dynamicallycontribute 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 towardzones of tissue damage. Chemokines produced in association with neuroinflammatory responses likely actas chemoattractants for neural progenitors during brain injury. Whether NPC cross the BBB from bloodremains unclear. We propose that systemic NPC can migrate across the BBB and promoteneuroprotection while attenuating neuroinflammation in HIV-1 encephalitis (HIVE). We will studymechanisms governing NPC migration and their effect on the BBB using the pathophysiologically relevantassumption of chemokine overproduction in neuroinflammation. We will investigate how migration across theBBB alters how NPC differentiate into neurons and glia and the effects of NPC on the BBB from within thebrain. Strategies in this program grant are being developed that enable a broad spectrum of anti-retroviraland 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 anattractive specific way to facilitate anti-retroviral or anti-inflammatory drug delivery, it is currently unknownhow NP-containing leukocytes affect BBB function during migration or from the 'brain' side of the barrier andperhaps even more importantly how they affect neuronal and glial integrity. Therefore, we will address thepathways and nanotoxicology for migration of macrophages across BBB with drug laden NP. We willevaluate the cell's ability to move and affect the integrity and function of the BBB and to affect diseaserelatedneuropathology. These cell-based novel therapeutic approaches are interdisciplinary and showynergy 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 modelsfor HIVE will be employed to validate in vitro observations using in vivo imaging techniques allowingassessment of BBB integrity, neuronal injury, and neuroinflammation.
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