Biomarker signatures of biological, chemical, or psychological stress

描述(由申请人提供)： 它假设人类暴露在环境压力(生物、化学、物理和心理)下会导致神经-内分泌-免疫轴的变化。这些变化会引起血液中反映生物标记物水平变化的分子成分的变化。败血症患者和类风湿性关节炎患者将被用作原型应激个体，以识别和量化血清蛋白的存在，这些蛋白已经增加、减少或显示出表位修饰的表达。这些分子特征将形成特定生物标志物签名的基础，这些签名是应激状态下人类个体的特征。初步实验证明，生物、化学和心理压力会改变血浆蛋白表达水平，这在一定程度上是由于炎症和/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应激的预测因子，这些因素的特征将为应激的程度和暴露的严重程度提供预后。单个生物标志物预计与炎症相关的调节途径有关：抗炎、氧化剂：抗氧化剂和天然免疫过程，然后将在人源化小鼠中暴露于三种原型应激源：镉、冷束缚和李斯特菌感染后进行量化。该计划将描绘和量化相关生物标志物的正常基础和响应血浆浓度，并使用一种采用光栅耦合表面等离子体共振成像(GCSPRI)的新型生物传感器来验证它们的分析。GCSPRI是一个微阵列平台，它将利用自动化诊断系统近乎实时地实现对这些生物标记物特征的多路检测。除了应激源引起的血浆成分变化外，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。要评估的生物标记物包括凝血因子、细胞因子、应激蛋白、神经肽、抗氧化酶和经过硫醇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在这项工作中识别的生物标记物特征的影响。在这项工作结束时，我们将确定特定的生物标志物特征，这些特征既是特定特征的诊断，也是对压力的诊断和对应激个体的治疗管理的表征。

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.