Bioinformatics for Immune Response Biosignature Analyses

描述（由申请人提供）：我们的快速通道I期目标是定义和原型一个新的计算（生物信息学）框架，用于包括生物战剂在内的传染病的先天免疫反应生物特征分析。该框架将动态贝叶斯网络学习和建模技术与“智能软件代理”（ISA）技术相结合，能够对100多种时间过程同时测量的生物标志物（生物特征）进行定量和定性分析。我们认为，感染因子产生独特的时间生物特征，可以通过同时测量多种循环分子生物标志物（细胞因子、趋化因子和其他待定）来观察，这些分子生物标志物是宿主先天免疫和炎症反应机制不可或缺的一部分。一种新的计算方法对于解码分子反应和相互作用过程的相关复杂性至关重要，这种相互作用过程独特地模拟和识别感染因子。我们的方法分析了感染初期循环蛋白变化的时间模式及其进展，以揭示独特的蛋白质组水平“生物特征”。这一新框架将大大提高该行业在蛋白质组学水平上分析复杂的同时蛋白质相互作用和疾病时间过程调查的能力，而不仅仅是循环蛋白质。我们第一阶段的里程碑是开发一个原型框架，并展示其概念和可行性。我们将完善我们的框架，并在II期努力下继续开发，并使用受感染因子挑战的体内小鼠模型验证我们的框架。在II期，我们将整合我们的平台与Luminex LapMAP微珠流式细胞仪免疫分析仪器进行通信。该仪器可以同时从< 50微升的血清样品中测量多达100种不同的细胞因子/蛋白质/ snp。这是Seralogix基于web的即时护理平台的核心技术，该平台正在商业开发中，作为该提案的实物贡献。我们的长期目标是将基于蛋白质组学的即时诊断平台商业化，用于人类传染病（包括BWAs）的症状前检测。我们设想该平台将具有双重用途，以支持一线医生对突发事件和生物恐怖主义感染病原体的治疗和诊断，这些病原体对公共卫生和国土安全非常重要。该平台旨在使国家反生物恐怖主义防御平台对国家防范恐怖主义威胁至关重要。对任何疑似BWA感染的人进行症状前检测的重要性是显而易见的，这不仅对他或她本人的立即治疗，而且对避免灾难性的国家卫生灾难也是至关重要的。一个由工业界和学术界组成的独特的多学科团队已经为第一阶段和第二阶段组装起来。

DESCRIPTION (provided by applicant): Our Fast Track Phase I objective is to define and prototype a new computational (bioinformatic) framework for innate immune response biosignature analyses of infectious diseases including biowarfare agents. The framework combines Dynamic Bayesian Network learning and modeling techniques with "Intelligent Software Agent" (ISA) technology to enable quantitative and qualitative analysis of over 100 time-course simultaneously measured biomarkers (biosignatures). We believe that infectious agents produce unique temporal biosignatures that can be observed by simultaneously measuring multiple circulating molecular biomarkers (cytokines, chemokines and others TBD) that are integral to the host's innate immune and inflammatory response mechanisms. A new computational methodology is essential for decoding molecular responses and the associated complexities of interacting processes that uniquely model and identify an infectious agent. Our methodology analyzes temporal patterns of change of circulating proteins during the initial onset of infection and its progression to reveal unique proteome-level "biosignatures." This new framework will substantially advance the industry's capability to analyze complex simultaneous protein interactions and time-course investigations of diseases at the proteomic level and not just for circulating proteins. Our Phase I milestone is to develop a prototype framework and demonstrate its concept and feasibility. We will refine our framework and continue development under Phase II efforts and validate our framework using in vivo mice models challenged by infectious agents. In Phase II, we will be integrating our platform to communicate with the Luminex LapMAP microbead flow cytometry immunoassay instrument. This instrument can measure up to 100 different cytokines/proteins/SNPs, simultaneously from a serum sample < 50 microliters. This is the core technology for Seralogix's web based point-of-care platform under commercial development being leveraged as in-kind contribution for this proposal. Our long-term objective is to commercialize a proteomics-based point-of-care diagnostics platform for the presymptomatic detection of human infectious diseases, including BWAs. We envision the platform will have dual-use applications to supped the front-line physicians' therapeutics and diagnosis of emergent and bioterrorism infectious agents that are of great concern to public health and homeland security. The platform is intended to enable a National Counter-Bioterrorism Defense Platform critical to the Nation's preparedness against terrorist threats. The criticality of pre-symptomatic detection of any person suspected of BWA infection is obvious, not only for his or her own immediate treatment but also for the avoidance of a catastrophic national health disaster. A unique multidisciplinary team of industry and academia has been assembled for Phase I and Phase II.