2007 NIH Director's Pioneer Award Program (DP1)

这项提案描述了一个多学科研究计划，旨在 开发、验证和传播微流控技术，用于定量 蛋白质聚集与衰老的研究。蛋白质聚集与 老龄化和一些影响质量和持续时间的人类疾病 生活的一部分。蛋白质聚集的许多基本方面仍然难以捉摸， 包括蛋白质聚集和毒性之间的联系，以及 蛋白质聚集与血管内皮细胞瘤的发生和发展 疾病。将开发微流控平台来了解这些复杂的情况 自下而上和自上而下的流程。自下而上，新的 基于液滴的微流控系统将被开发来表征 定量研究蛋白质聚集与体外毒性之间的关系。 该系统将允许可重现的实时生成、操作和 体外和体内毒性筛选用聚集体的特性。 在这些装置中获得的毒性模式的多维统计分析 可能会阐明蛋白质聚集和毒性之间的联系，澄清 针对聚集的现有候选药物的作用机制，以及 加快新药和药物鸡尾酒研发。自上而下，微流控 将开发技术来诱导和监测体内聚集 时空分辨率高，并观察衰老、生理学的影响 状态、神经元活性和候选药物的存在对启动和 蛋白质聚集性疾病的进展。这两项技术将是 一起用于了解蛋白质聚集和衰老，并可能导致新的 控制这些过程的假说和分子。

This proposal describes a multi-disciplinary research program that aims to develop, validate, and disseminate microfluidic technologies for quantitative studies of protein aggregation and aging. Protein aggregation is associated with aging and with a number of human diseases that affect both quality and duration of life. Many fundamental aspects of protein aggregation remain elusive, including connections between protein aggregation and toxicity, and the connection between protein aggregation and initiation and progression of diseases. Microfluidic platforms will be developed to understand these complex processes from both bottom-up and top-down perspectives. Bottom-up, new droplet-based microfluidic systems will be developed to characterize quantitatively the connection between protein aggregation and toxicity in vitro. This system will allow the reproducible real-time generation, manipulation, and characterization of aggregates for in vitro and in vivo toxicity screens. Multidimensional statistical analysis of toxicity patterns obtained in these devices may elucidate the connection between protein aggregation and toxicity, clarify the mechanism of action of existing drug candidates that target aggregation, and accelerate development of new drugs and drug cocktails. Top-down, microfluidic technologies will be developed to induce and monitor aggregation in vivo with high spatiotemporal resolution, and to observe the effects of aging, physiological state, neuronal activity, and presence of drug candidates on the initiation and progression of protein aggregation diseases. These two technologies will be used together to understand protein aggregation and aging, and may lead to new hypothesis and molecules for controlling these processes.