Chemical design of amyloid targeting fluorescent probes

淀粉样蛋白靶向荧光探针的化学设计 项目摘要 大脑中淀粉样斑块的沉积是许多神经退行性疾病的普遍特征。 比他们的临床症状早几年。因此，对淀粉样斑块的特异性检测可以 被用作诊断神经退行性变的生物标记物，使疾病有机会得到改善 治疗性干预。我们最近设计了一系列新的荧光探针，可以标记 组织中的淀粉样蛋白。重要的是，我们的结果第一次表明，这些探针增强了 淀粉样蛋白的可视化，也使得能够以颜色计量学区分淀粉样蛋白作为以下函数 它们的蛋白质组成。这种独特的能力可以实现对特定目标的准确诊断/监控 神经退行性疾病，从而帮助选择适当的疗程。在此，我们建议 评估允许合理设计荧光探针的结构和电子参数 淀粉样蛋白歧视。这项工作将产生对固有的具有根本意义的新信息 淀粉样蛋白的特性和对新诊断开发的即刻适用性。的具体目标 这项建议是：a)发展和实验检验合理设计淀粉样蛋白的理论模型。 靶向荧光探针(ATFP)；b)使用合理设计的ATFP来表征淀粉样蛋白 它们的相对介电系数值，并开发基于ATFP的指纹分析；c)开发ATFP 通过改变其化学/电子结构来增强光学/生物性能；以及d)评估 ATFP在溶液和组织中的生物物理性质。

Chemical design of amyloid targeting fluorescent probes Project Summary Deposition of amyloid plaques in the brain represents a universal feature of many neurodegenerative diseases and precedes their clinical symptoms by several years. Thus, the specific detection of amyloid plaques can be used as a biomarker for the diagnosis of neurodegeneration, allowing the opportunity for disease-modifying therapeutic intervention. We have recently designed a new family of fluorescent probes that can label amyloids in tissue. Importantly, our results demonstrate, for the first time, that these probes enhance visualization of amyloids and also make it possible to colorimetrically differentiate the amyloids as a function of their protein composition. This unique ability may enable accurate diagnosis/monitoring of specific neurodegenerative diseases, thereby aiding in selection of a proper course of treatment. Here, we propose to evaluate the structural and electronic parameters that allow the rational design of fluorescent probes for amyloid discrimination. This work will result in new information of fundamental significance to the inherent properties of amyloids and immediate applicability to the development of new diagnostics. The specific aims of this proposal are to: a) develop and experimentally test a theoretical model for the rational design of amyloid targeting fluorescent probes (ATFPs); b) use rationally designed ATFPs to characterize amyloids based on their relative permittivity values and develop an ATFP-based fingerprinting assay; c) develop ATFPs with enhanced optical/biological properties by modifying their chemical/electronic structure; and d) evaluate the biophysical properties of ATFPs in solution and in tissue.