BWA Host-Pathogen Innate Immune S/W Analysis Tools

描述（由申请人提供）：这项第二阶段SBIR研究是生物防御资助的第一阶段的延续，目的是开发新的计算工具，以发现宿主-病原体遗传相互作用机制，并创建用于分析和预测先天性和适应性免疫的数学模型。具有用于识别遗传调节的宿主免疫应答的新计算方法将显著有助于推进我们对病原微生物的强大防御至关重要的分子靶标和免疫机制的理解。这对于生物战剂（BWA）和其他高度公共卫生关注的常见疾病，特别是对于新疫苗和免疫药物的安全和有效开发，是极其重要的知识。此外，有助于将大量原始基因组/蛋白质组学和生理学数据转化为可操作知识的新计算工具将有助于指导和加速研究人员对新疫苗、佐剂和免疫药物的研究。这不仅与生物防御有关，而且与许多其他病原体和疾病有关-特别是在最终从动物模型预测人类反应的重要研究中。第一阶段产生了很好的结果表明，我们的计算工具的基础上动态贝叶斯网络（DBN）可以用来发现机制的过程和模型的宿主免疫反应BWAs和其他传染病。与第一阶段一样，我们的第二阶段计算工具将基于DBN的统计/概率能力，我们计划扩展DBN，以实现和验证多条件比较研究，从而发现和创建预测性免疫反应模型。这些模型是从基因、蛋白质和生理因素的时间过程模式中推导出来的，我们称之为宿主的“生物特征”。我们的计算方法的一个创新是能够包括时间过程数据（基因，蛋白质和生理数据）与先前的生物学知识（即调控途径，基因-基因/蛋白质-蛋白质关系，基因同源性，功能本体等）融合。我们相信这显著地推进了新的免疫组分的发现和基于机制的免疫应答模型的创建。第二阶段的目标是：1）实施创新的多条件比较计算方法，该方法被设计为能够发现潜在的宿主-病原体遗传机制，以及2）在选定的一组病原体上验证我们的机制发现和建模方法（B.羊种布氏杆菌病（Brucellosis）、B.炭疽病（炭疽热）、粗球孢子菌（谷热）和流感）和疫苗（基因工程和减毒）。新疫苗和药物的研究产生了大量的“原始”免疫基因组学、蛋白质组学和生理反应数据。这些“原始”数据必须转化为可操作的知识，以指导和加速研究人员对新疫苗、佐剂和免疫药物的研究。Seralogix用于识别遗传调节的宿主免疫反应的新计算方法将大大有助于促进我们对分子靶点和免疫机制的理解，这些靶点和免疫机制对于抵御病原微生物至关重要。这不仅与生物防御有关，而且与许多其他病原体和疾病有关-特别是在最终从动物模型预测人类反应的重要研究中。Seralogix认为，这些工具将能够发现新的免疫机制，因此具有巨大的商业潜力。

DESCRIPTION (provided by applicant): This Phase II SBIR research is the continuation of a Biodefense funded Phase I with the objective to develop new computational tools to discover host-pathogen genetic interactive mechanisms and create mathematical models for analyzing and predicting innate and adaptive immunity. Having new computational methods for identifying genetically regulated host immune response will significantly aid in advancing our understanding of the molecular targets and immunologic mechanisms critical to robust defense against pathogenic microbes. This is extremely important knowledge for biowarfare agents (BWA) and other common diseases of high public health concern especially for the safe and effective development of new vaccines and immunotherapeutic drugs. Further, new computational tools to help transform volumes of raw genomic/proteomic and physiologic data to actionable knowledge will help guide and accelerate researchers' investigations for new vaccines, adjuvants, and immunotherapeutic drugs. This is relevant, not only to biodefense, but for many other pathogens and diseases -- especially in studies where it is important to eventually predict human response from animal models. Phase I produced excellent results in demonstrating that our computational tools based on dynamic Bayesian networks (DBNs) can be used to discover mechanistic processes and model the host immune response to BWAs and others infectious diseases. As in Phase I, our Phase II computational tools will be based on the statistical/probabilistic power of DBNs which we plan to expand to enable and validate for multi-conditional comparative studies leading to mechanistic discovery and creation of predictive immune response models. These models are derived from the time-course patterns of genes, proteins and physiologic factors which we call the host's "biosignature". An innovation of our computational approach is the ability to include time-course data (gene, protein, and physiologic data) fused with prior biological knowledge (i.e. regulatory pathways, gene-gene/protein-protein relations, gene homologies, functional ontologies, etc.) which we believe significantly advances the discovery of novel immunologic components and the creation of mechanistic-based immune response models. The Phase II goals are to: 1) implement an innovative multi-conditional comparative computational methodology designed to enable the discovery of underlying host-pathogen genetic mechanisms, and 2) the validation of our mechanistic discovery and modeling methodology on a select set of pathogens (B. melitensis (Brucellosis), B. anthracis (anthrax), Coccidioides immitis (Valley fever), and Influenza) and vaccines (genetically engineered and attenuated). The investigation of new vaccines and drugs are producing huge volumes of "raw" immunologic genomic, proteomic and physiological response data. This "raw" data must be transformed into actionable knowledge to guide and accelerate researchers' investigations for new vaccines, adjuvants, and immunotherapeutic drugs. Seralogix's new computational methods for identifying genetically regulated host immune response will significantly aid in advancing our understanding of the molecular targets and immunologic mechanisms critical to robust defense against pathogenic microbes. This is relevant, not only to biodefense, but for many other pathogens and diseases -- especially in studies where it is important to eventually predict human response from animal models. Seralogix believes that such tools will be capable of discovering novel immunologic mechanism and thus have significant commercial potential.