2007 NIH Director's Pioneer Award Program (DP1)

该提案描述了一个多学科的研究计划，旨在 开发、验证和推广微流体技术， 蛋白质聚集和衰老的研究。蛋白质聚集与 老化和一些影响质量和持续时间的人类疾病 生命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， 蛋白质聚集和蛋白质聚集的起始和进展之间的联系 疾病微流体平台将被开发来理解这些复杂的 从自下而上和自上而下的角度进行流程。自下而上，全新 将开发基于液滴的微流控系统， 定量研究了蛋白质聚集与体外毒性之间的关系。 该系统将允许可再现的实时生成、操作和 用于体外和体内毒性筛选的聚集体的表征。 对这些器械中获得的毒性模式进行多维统计分析 可以阐明蛋白质聚集和毒性之间的联系，澄清 靶向聚集的现有候选药物的作用机制，以及 加快新药和鸡尾酒药物的开发。自上而下，微流体 将开发诱导和监测体内聚集的技术， 高时空分辨率，并观察衰老，生理 状态、神经元活性和起始时候选药物的存在， 蛋白质聚集疾病的进展。这两项技术将在 一起使用，以了解蛋白质聚集和老化，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.