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

败血症，全身炎症和器官衰竭，由压倒性的和不平衡的感染反应引发，导致巨大的人类和医疗保健成本。在全球范围内，每年有超过3000万人受到影响，其中至少四分之一会死亡。这些类别包括身体残疾、精神残疾和心理残疾。目前，还没有特效的治疗方法。对于癌症患者来说，根据肿瘤的分子特征进行个性化治疗是一种很好的做法。目前迫切需要对脓毒症患者进行同样的治疗。我们已经确定了DNA(DNA甲基化标记)上的标签，可以对脓毒症患者和非败血症患者进行分类，对不良结局(死亡和器官衰竭)的可能性以及对治疗(降压药)的反应。与此同时，我们的合作伙伴已经开发并申请了一种护理点设备，该设备使用创新的微流控方法从全血中分离DNA。我们建议采用这项技术来开发能够使用全血对患者的DNA标记进行自动测量的原型；测试我们的设备库中的DNA和全血样本；使用预测建模来整合临床和分子数据，以在独立的队列中验证结果预测和治疗反应；并前瞻性地在区域世界的情况下测试我们的原型和精确标记的性能。这项技术和生物标记物检测方法以前从未尝试过用于脓毒症。这项提议汇集了生物工程师、健康研究科学家、生物信息学家、医生和临床生物化学家。成功的完成将提供一种芯片上实验室技术，该技术采用由先进的专利离心式微流控技术驱动的低成本、可工业化制造的聚合物微流控设备，有望在整合和部署基因组知识的方式方面进行颠覆性创新，该实用设备将影响临床实践和危重患者的护理。

Sepsis, whole body inflammation and organ failure triggered by an overwhelming andunbalanced 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. Thesequelae include physical, mental, and psychological disability. Currently, no specifictreatments exist. For cancer patients, personalizing treatment on the basis of molecularcharacteristics of a tumor is simply good practice. There is an urgent need to do the same forsepsis. 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 totherapy (blood pressure medications). In parallel, our partners have developed and patenteda point-of-care device that uses an innovative microfluidic approach to isolate DNA fromwhole blood. We propose to adapt this technology to develop a prototype able to performautomated measurements of DNA marks from patients using whole blood; to test our deviceon banked DNA and whole blood samples; to use predictive modeling to integrate clinical andmolecular data to validate outcome prediction and response to therapy in an independentcohort; and to test the performance of our prototype and precision marks prospectively in areal-world situation. Both the technology and biomarker detection approaches have neverbeen tried for sepsis before. This proposal brings together bioengineers, health researchscientists, bioinformaticians, physicians and clinical biochemists. Successful completion willprovide a Lab-on-chip technology employing low-cost industrially manufacturable polymermicrofluidic devices powered by an advanced patented centrifugal microfluidic technology thatpromises to be a disruptive innovation in the way to integrate and deploy genomic knowledgepractical devices that will impact clinical practices and the care of the critically ill.