Reactive oxygen species (ROS) and oxidative stress are major contributors to the pathogenesis of important neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and cerebrovascular disease. The central nervous system comprises the most oxidatively active organ system in the body. Under normal physiological conditions, brain activity- and the neuronal and synaptic processes underpinning this activity- generates free radical species that progressively damage essential biomolecules (nucleic acids, lipids, proteins). Under a variety of pathological states, ROS-mediated oxidative damage is dramatically accelerated and leads to irreversible brain damage, cerebral dysfunction, cognitive decline, and death. An overwhelming body of scientific evidence now points to ROS-mediated oxidative damage as a key pathogenic pathway involved in the earliest stages of many neurodegenerative diseases. Technology to quantitatively detect and monitor ROS is critical for understanding and treating these disorders, Currently available ROS assay systems (1) detect only a single (or at most a limited number) of biological relevant species, (2) chemically interact with the species under analysis, (3) require complex, time-consuming, labor-intensive analytical processing, and (4) are temporally disconjugate with respect to the short half-lives of most biologically relevant ROS species. This last point is especially important and frequently overlooked. By the time analytical measurements are initiated using conventional methods, significant loss of signal has accrued due to decomposition. For all of these reasons, available ROS detection technology does not meet the analytical standards required for modern biomedical research. A transformative research program to develop an innovative nanotechnology-based toolkit for measuring ROS in biological systems is proposed. A non-enzymatic probe (nanoceria), integrated sensor components, and simplified detection procedure will enable sequential analytical operation on a small, inexpensive chip. An outstanding merit of the proposed approach is the use of a versatile nanoparticle detector array that generates a detectable amperometric signal following oxidation state alterations induced by interaction with ROS. The proposed technology development program will enable fundamental studies of neurodegenerative disease pathogenesis that have not been previously possible.
Broader Impact The outcome of this research is linked to high-impact national healthcare priorities. The program will establish an interdisciplinary collaboration between the University of Central Florida; Boston University School of Medicine, College of Engineering, and Photonics Center; and the National Institutes of Health (NIH)-funded Alzheimer's Disease Center at Boston University. Education and training are essential components and leverages graduate and undergraduate teaching opportunities, coursework (including a highly successful internet-based off-site access program), and summer research programming. Additional emphasis will focus on minority and K-12 students who participate in on-campus interdisciplinary educational programs at both institutions. The proposed research and educational activities will provide a unique cross-dimensional (nano-to-meso scale) and cross-disciplinary (materials, electrochemistry, fluid mechanics, electrical engineering, neurobiology) approach for development of innovative non-enzyme biosensors with far-ranging biomedical impact. This research will deepen understanding of electrochemical and biochemical reactions at the nanoscale and affords significant potential to provide new insights into the pathogenic role of ROS in human neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and stroke.
