ELECTRONIC SENSING OF NEURODEGENERATIVE DISEASE FIBRILS

我们将开发一种电子技术来检测纤维聚集体，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（检测到100个蛋白质分子）表明，我们技术的灵敏度提高，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原纤维来对患者进行非侵入性筛查，并提供用于评估临床试验中药物功效的定量方法。该技术可以很容易地扩展到基于MEMS（微电子和机械系统）的阵列测定，以多重筛选抑制原纤维形成的药物。该技术还将能够快速筛选嵌套的肽组，以鉴定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该技术，因为它是一个重要的生物学问题，β-淀粉样蛋白变体的原纤维形成已经在体外得到了很好的表征，并且已经确定了治疗干预的可能靶点，即原纤维。然而，该技术可用作在高通量系统中检测任何蛋白质-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：神经退行性疾病特征性纤维聚集体的快速电子检测将允许测试的商业开发，以筛选疾病的症状前患者，客观地监测症状患者对治疗的反应，并筛选阻断纤维形成或其掺入聚集体的药物。

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.