Systems Approach to Innate Immunity-Inflammation-Sepsis

在美国，最近的估计表明，每年有超过75万名患者处于发展为感染性休克的高风险状态，死亡率高达60%。因此，与这种综合征相关的社会和经济代价巨大。鉴于其发病率高、预后差的特点，我们建议对先天免疫系统及其与获得性免疫系统的接口进行基础研究。我们承认严重脓毒症/休克的病理生理学极其复杂。然而，毫无疑问的是，通常从感染--)正常的全身反应(败血症)--)严重的败血症--)休克 而这一序列中的主要事件是感染。也有重要证据表明，感染部位(S)炎症过程的强度决定了全身对感染反应的严重程度，从而决定了严重脓毒症和休克的发生。我们认为，接近这样一个复杂系统的唯一方法是使用适当的细胞和动物模型系统，并在分析中应用系统生物学的原理。为了实现这一目标，我们聚集了具有许多不同科学背景和专业的研究人员，包括尖端生物信息学、基因组和蛋白质分析、细胞生物学、先天和获得性免疫研究、生物网络建模。 最重要的是，我们将先天免疫领域的专家与基因组学、蛋白质组学和生物信息学领域的专家等“新科学血液”结合起来。我们认为，在这个胶水赠款的背景下，调查人员的这种组合将在我们高度互动和相互依赖的环境中，极大地扩大这一领域新概念的形成。这一努力将为科学界进行大量假设驱动的研究奠定基础，包括基础和临床研究。这些研究还将确定潜在的新药靶点，可能导致败血症和休克的新疗法。这将直接影响这些危重病人的临床结局。

In the United States, recent estimates suggest that more than 750,000 patients per year are at high risk for developing septic shock with mortality rates reaching 60%. Thus there are huge societal and financial costs associated with this syndrome. Because of its high incidence and poor prognosis, we propose basic research focused on the innate immune system and its interface with the adaptive immune system. We acknowledge that the pathophysiology of severe sepsis/shock is exceedingly complex. There is little doubt, however, that there is often a progression from infection --) normal systemic response (sepsis) --) severe sepsis --) shock and that the primary event in this sequence is infection. There is also important evidence that the intensity of the inflammatory process at the site(s) of infection determine the severity of the systemic reaction to infection, and thus the occurrence of severe sepsis and shock. It is our contention that the only means to approach such a complex system is to use appropriate cellular and animal model systems and apply the principles of systems biology in their analysis. To accomplish this we have brought together investigators with many different scientific backgrounds and specialties that include cutting-edge bioinformatics, genomic and proteomic analyses, cell biology, studies of innate and adaptive immunity, biological network modeling etc. Most importantly, we have combined experts in the field of innate immunity with "new scientific blood" such as experts in the fields of genomics, proteomics and bioinformatics. It is our contention that in the context of this GLUE GRANT this combination of investigators will, in our highly interactive and interdependent setting, substantially expand the formulation of new concepts for this field. This effort will form the basis for a great many hypothesis-driven studies by the scientific community at-large, both basic and clinical. These studies will also identify potential new drug targets that could lead to new therapies for sepsis and shock. This would directly impact the clinical outcome of these critically ill patients.