KSEF RDE: Nanoparticle-Induced Dysfunction of Brain Endothelial Cells and Disruption of the Blood-Brain Barrier

Nanotechnology uses engineered materials or devices at the nanometer scale, typically ranging from 1 to -100 nanometers. Nanotechnology approaches are used for treatment, diagnosis, monitoring, and controlling of biological systems. For example, nanotechnology provides new means for targeted drug delivery into the CNS and the development of pharmacological, therapeutic and diagnostic agents for a variety of CNS disorders. However, nanoparticles preserve high surface reactivity and may have negative health and environmental impacts. Nanoparticles can readily travel throughout the body, deposit in target organs, and lodge in the mitochondria. Therefore, potential toxic effects of manufactured nanoparticles are the emerging concern in human health. In the present proposal, we hypothesize that exposure to nanoparticles of aluminum oxide (nanoalumina) disrupts integrity of the cerebral endothelium through redox-regulated signaling mechanisms. We propose that nano-alumina can alter mitochondrial membrane potential, induce cellular oxidative stress, stimulate redox-regulated signaling pathways, and decrease expression of tight junction proteins in brain endothelial cells. Tight junctions seal brain endothelial cells along the cerebral microvessels and are responsible for low paracellular permeability and high electrical resistance of the brain endothelium. Therefore, alterations of tight junction protein expression and dysfunction of the brain endothelial cells can directly affect the integrity of the blood-brain barrier (BBB), leading to the brain injury. The hypothesis of this grant proposal will be studied using a variety of cellular and molecular biology approaches, combined with functional assays to determine integrity of the brain endothelium. The results of the present proposal are likely to increase our knowledge on vascular toxicity of nanoparticles and to identify novel mechanisms of nano-alumina-induced disruption of the BBB. The findings resulting from the present proposal are applicable to neuropathological disorders where alumina, nanoparticles, and/or disruption of the BBB play detrimental roles.