Collaborative: Regenerative Nanosensors for Quantitative Assessment of Oxidative Stress in Neurodegeneration

智力价值活性氧物种(ROS)和氧化应激是阿尔茨海默病、帕金森病和脑血管疾病等重要神经退行性疾病的主要致病因素。中枢神经系统是人体内氧化活性最强的器官系统。在正常的生理条件下，大脑活动--以及支撑这种活动的神经元和突触过程--产生自由基物种，逐渐损害基本的生物分子(核酸、脂类、蛋白质)。在各种病理状态下，ROS介导的氧化损伤急剧加速，导致不可逆转的脑损伤、脑功能障碍、认知功能减退和死亡。大量科学证据现在指出，ROS介导的氧化损伤是许多神经退行性疾病早期涉及的关键致病途径。定量检测和监测ROS的技术对于理解和治疗这些疾病至关重要，目前可用的ROS分析系统(1)仅检测单个(或至多有限数量)生物相关物种，(2)与被分析物种的化学相互作用，(3)需要复杂、耗时、劳动密集型的分析处理，以及(4)相对于大多数生物相关ROS物种的短暂半衰期而言，在时间上是不一致的。最后这一点特别重要，但经常被忽视。当使用常规方法开始分析测量时，由于分解已经累积了显著的信号损失。由于所有这些原因，现有的ROS检测技术不符合现代生物医学研究所需的分析标准。提出了一项变革性的研究计划，旨在开发一种基于纳米技术的创新工具包，用于测量生物系统中的ROS。非酶探针(纳米陶瓷)、集成的传感器组件和简化的检测程序将使在一个小而便宜的芯片上进行顺序分析操作成为可能。提出的方法的突出优点是使用多功能纳米颗粒检测器阵列，该阵列在与ROS相互作用引起的氧化状态改变后产生可检测的安培信号。拟议的技术开发计划将使神经退行性疾病发病机制的基础研究成为可能，这在以前是不可能的。更广泛的影响这项研究的结果与高影响力的国家医疗保健优先事项有关。该计划将在中佛罗里达大学、波士顿大学医学院、工程学院和光子学中心以及波士顿大学由国家卫生研究院(NIH)资助的阿尔茨海默病中心之间建立跨学科合作。教育和培训是必不可少的组成部分，并利用研究生和本科生的教学机会、课程作业(包括非常成功的基于互联网的非现场访问计划)和暑期研究规划。额外的重点将集中在少数族裔和K-12学生，他们参加了这两所大学的校园跨学科教育计划。拟议的研究和教育活动将为开发具有广泛生物医学影响的创新型非酶生物传感器提供一种独特的跨维(纳米到介观尺度)和跨学科(材料、电化学、流体力学、电气工程、神经生物学)的方法。这项研究将加深对纳米级电化学和生化反应的了解，并为ROS在人类神经退行性疾病(包括阿尔茨海默病、帕金森病和中风)中的致病作用提供新的见解。

Intellectual MeritReactive 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 ImpactThe 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.