Biomarker signatures of biological, chemical, or psychological stress

描述（由申请人提供）： 据推测，人类暴露于环境压力（生物，化学，物理和心理）导致神经内分泌免疫轴的改变。这些变化引起血液分子成分的变化，反映生物标志物水平的变化。脓毒症患者和类风湿性关节炎患者将被用作原型应激个体，以鉴定和定量增加、减少或显示表位修饰表达的血清蛋白的存在。这些分子特征将形成特定生物标志物签名的基础，这些生物标志物签名是应激人类个体的特征。初步实验证明，生物，化学和心理应激改变血浆蛋白表达水平，这部分是由于炎症和/或氧化过程。由于我们认为不同形式的应激源调节内分泌，免疫和神经系统之间的相互作用途径，我们预计免疫，内分泌和神经系统因素将是压力的预测因子，这些因素的配置文件将提供预后的压力程度和严重程度的曝光。预测与炎症相关的调节途径相关的个体生物标志物：抗炎，氧化剂：抗氧化剂和先天免疫过程，然后将在暴露于三种原型应激源后的人源化小鼠中进行定量：镉，冷约束和肠道感染。该计划是描绘和量化相关生物标志物的正常基础和响应血浆浓度，并使用采用光栅耦合表面等离子体共振成像（GCSPRI）的新生物传感器验证其分析。GCSPRI是一个微阵列平台，它将使这些生物标志物的签名与自动诊断系统在近真实的时间的多重检测。除了应激诱导的血浆成分变化外，我们还将评估血液白细胞抗原的变化;淋巴细胞对炎症产物和氧化剂特别敏感。血液制品是以最小的侵入性获得的，它们代表了对应激源的全身反应的最佳组合。GCSPRI技术将与Luminex技术进行平行测试。待评价的生物标志物包括凝血因子、细胞因子、应激蛋白、神经肽、抗氧化酶和具有巯基相关修饰的正常血浆蛋白。最后，我们将评估不同的应激反应能力对这项工作中已经确定的生物标志物特征的影响。在这项工作的结论，我们将确定特定的生物标志物的签名，这两个诊断的特定签名，这将是非常宝贵的压力的诊断，并强调个人的治疗管理的表征。

DESCRIPTION (provided by applicant): It is hypothesized that human exposures to environmental stresses (biological, chemical, physical and psychological) result in alterations to the neuro-endocrine-immune axis. These changes provoke shifts in molecular components of the blood that reflect changes in biomarker levels. Septic patients and rheumatoid arthritis patients will be used as prototype stressed individuals to identify and quantify the presence of serum proteins that have increased, decreased, or which display epitope-modified expression. These molecular features will form the basis of specific biomarker signatures that are characteristic of stressed human individuals. Preliminary experiments document that biological, chemical, and psychological stress alters plasma protein expression levels, which in part, are due to inflammation and/or oxidative processes. Since we suggest the different forms of stressors modulate the interactive pathways between the endocrine, immune, and nervous systems, we anticipate that immune, endocrine, and nervous system factors will be predictors of stress and that the profiles of these factors will provide prognosis for the degree of stress and the severity of the exposure. Individual biomarkers, which are predicted to relate to regulatory pathways associated with inflammation: anti-inflammation, oxidants: anti-oxidants, and innate immune processes, will then be quantified in humanized mice after exposure to three prototype stressors: cadmium, cold-restraint, and listerial infection. The plan is to delineate and quantify the normal basal and responsive plasma concentrations of relevant biomarkers and to validate their analysis with a new biosensor employing grating- coupled surface plasmon resonance imaging (GCSPRI). GCSPRI is a microarray platform that will enable the multiplexed detection of these biomarker signatures with an automated diagnostic system in near real time. In addition to stressor-induced changes in plasma constituents, we will evaluate changes to blood leukocyte antigens; lymphocytes are especially sensitive to inflammatory products and oxidants. Blood products are obtained with minimal invasiveness, and they represent the best composite of the systemic response to a stressor. The GCSPRI technology will be parallel tested against the Luminex technology. The biomarkers to be evaluated include blood clotting factors, cytokines, stress proteins, neuropeptides, antioxidant enzymes, and normal plasma proteins with thiol-related modifications. Finally, we will evaluate the consequences of different stress response capabilities on the character of the biomarker signatures that have been identified in this work. At the conclusion of this work we will have identified specific biomarker signatures that are both diagnostic of specific signatures, and which will be invaluable in both the diagnosis of stress, and the characterization of therapeutic management of stressed individuals.