Rapid Microfluidic-Based Point-of-Care Assessment of Epigenetic Marks for Diagnosis, Prognosis and Response to Therapy in Critical Illness

脓毒症，全身炎症和器官衰竭由压倒性和 对感染的反应不平衡，导致巨大的人类和卫生保健成本。在全球范围内， 每年有3000多万人受到影响，其中至少四分之一会死亡。这个 后遗症包括身体、精神和心理上的残疾。目前，没有具体的 治疗方法是存在的。对于癌症患者，以分子为基础的个性化治疗 肿瘤的特征就是很好的练习。我们迫切需要做同样的事情 败血症。我们已经确定了DNA上的标记(DNA甲基化标记)，可以区分脓毒症和 非败血症患者预后不良的可能性(死亡和器官衰竭)和对 治疗(降压药)。与此同时，我们的合作伙伴已经开发并获得了专利 一种使用创新的微流控方法从 全血。我们建议采用这项技术来开发一种能够执行 使用全血自动测量患者的DNA标记；以测试我们的设备 对储存的DNA和全血样本进行分析；使用预测建模将临床和 一项独立的分子数据用于验证结果预测和治疗反应 并对我们的原型和精度标记的性能进行前瞻性的测试 真实世界的情况。无论是技术还是生物标记物检测方法都从未 以前曾因败血症受审过。这项提案将生物工程师、健康研究 科学家、生物信息学家、内科医生和临床生物化学家。成功完成后将 提供采用低成本工业可制造聚合物的芯片实验室技术 由先进的专利离心式微流控技术提供动力的微流控装置 有望成为整合和部署基因组知识的颠覆性创新 将影响临床实践和危重病人护理的实用设备。

Sepsis, whole body inflammation and organ failure triggered by an overwhelming and unbalanced response to infection, incurs enormous human and health care costs. Globally, over 30 million people are affected each year, at least a quarter of whom will die. The sequelae include physical, mental, and psychological disability. Currently, no specific treatments exist. For cancer patients, personalizing treatment on the basis of molecular characteristics of a tumor is simply good practice. There is an urgent need to do the same for sepsis. We have identified tags on DNA (DNA methylation marks) that can classify septic vs. non-septic patients, the likelihood of poor outcomes (death and organ failure) and response to therapy (blood pressure medications). In parallel, our partners have developed and patented a point-of-care device that uses an innovative microfluidic approach to isolate DNA from whole blood. We propose to adapt this technology to develop a prototype able to perform automated measurements of DNA marks from patients using whole blood; to test our device on banked DNA and whole blood samples; to use predictive modeling to integrate clinical and molecular data to validate outcome prediction and response to therapy in an independent cohort; and to test the performance of our prototype and precision marks prospectively in a real-world situation. Both the technology and biomarker detection approaches have never been tried for sepsis before. This proposal brings together bioengineers, health research scientists, bioinformaticians, physicians and clinical biochemists. Successful completion will provide a Lab-on-chip technology employing low-cost industrially manufacturable polymer microfluidic devices powered by an advanced patented centrifugal microfluidic technology that promises to be a disruptive innovation in the way to integrate and deploy genomic knowledge practical devices that will impact clinical practices and the care of the critically ill.