ELECTRONIC SENSING OF NEURODEGENERATIVE DISEASE FIBRILS

我们将开发一种电子技术来检测纤维聚集，这是阿尔茨海默氏症和帕金森氏症等神经退行性疾病的特征。我们的初步结果(对100个蛋白质分子的检测)表明，我们技术的增强灵敏度可以检测到神经退行性疾病(如阿尔茨海默病)的最早生化证据。这将允许通过分析体液中的特征纤维对患者进行非侵入性筛查，并为临床试验中评估药物疗效提供一种定量方法。这项技术可以很容易地扩展到基于MEMS(微电子和机械系统)的阵列分析，以多路筛选抑制纤维形成的药物。这项技术还将使快速筛选嵌套的多肽集合，以识别参与原纤维形成的序列。我们选择阿尔茨海默病作为我们的模型系统来开发和测试这项技术，因为这是一个重要的生物学问题，β-淀粉样变异体的纤维形成在体外已经得到了很好的表征，并且已经确定了一个可能的治疗干预目标--原纤维。然而，该技术可以用作检测高通量系统中任何蛋白质-蛋白质、抗体-蛋白质或药物-蛋白质相互作用的通用工具。拟议的商业应用：对神经退行性疾病特有的纤维集合体进行快速电子检测将使测试的商业化发展成为可能，以筛查症状前患者的疾病，客观监测有症状患者的治疗反应，并筛选阻止纤维形成或将其合并到集合体中的药物。

We will develop an electronic technology to detect fibrillar aggregates, which are characteristic of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Our preliminary results (detection of 100 protein molecules) indicate that the enhanced sensitivity of our technology could enable the detection of the earliest biochemical evidence of a neurodegenerative disease, like Alzheimer's disease. This would allow the non-invasive screening of patients by analyzing bodily fluids for characteristic fibrils and provide a quantitative method for assessing the efficacy of drugs in clinical trials. The technology can readily be extended to a MEMS (microelectronic and mechanical system) based array assay to multiplex the screening of drugs to inhibit fibril formation. The technology will also enable the rapid screening of nested sets of peptides to identify sequences that participate in fibril formation. We have chosen Alzheimer's disease as our model system to develop and test the technology because it is an important biological problem, fibril formation of beta-amyloid variants has been well characterized in vitro and a likely target for therapeutic intervention, the protofibril, has been identified. However, the technology can be used as a general tool for detecting any protein-protein, antibody-protein or drug-protein interaction in a high-throughput system. PROPOSED COMMERCIAL APPLICATIONS: The rapid electronic detection of fibrillar aggregates characteristic of neurodegenerative diseases will allow for the commercial development of tests to screen pre-symptomatic patients for disease, to objectively monitor response to therapy in symptomatic patients and to screen for drugs that block fibril formation or their incorporation into aggregates.