Study of Chronic Fatigue Syndrome using comprehensive molecular profiling with ne

描述(由申请人提供)：本项目的意义在于慢性疲劳综合征(CFS)作为一个日益严重的公共卫生问题的规模和范围，以及当前急性疾病研究模型的不足，以解决影响身体多个调节系统的复杂疾病。这种疾病跨越种族、性别和社会经济地位，影响到社会的广泛部分，每年给美国经济造成的损失估计为90亿美元，医疗保健支出高达240亿美元。此外，并发症和并存可能是严重的，包括心血管疾病和癌症，这进一步增加了风险。研究表明，免疫、内分泌和神经系统都会受到影响。尽管这些系统的功能密切协作，但CFS仍在使用传统的逐块方法进行研究，重点放在单个神经内分泌和免疫组件的故障上。假设：我们假设CFS不仅是组件故障造成的，也许更重要的是连接这些组件的调节功能的显着恶化。我们将通过运动挑战来刺激应激反应及其对神经、内分泌和免疫系统的调节，以测试调节适应性。目的：本研究的目的是从三个方面提高我们对CFS发病机制的认识：(I)通过使用广泛的分子图谱来创建对身体几个调节系统的状态的全面评估；(Ii)通过使用信息论将这些不同的数据整合到描述这些生理系统之间相互作用的单一可解释的地图中；以及(Iii)通过使用网络理论的新元素来研究这些信号网络的结构，并分离可能是CFS特有的“连接”的变化。嵌入到这些地图中，我们还将捕捉到最重要的动态平衡控制对压力的动态反应。这种关于生物信息通过神经内分泌免疫网络传播的速度和方向的定量知识将被用作模拟治疗反应的基础。事实上，神经内分泌免疫反应的计算机模拟将被用于执行候选临床试验的计算机辅助设计，其方式与模拟用于培训机组人员的方式大致相同。通过将CFS模拟为一个改变但稳定的控制程序，可以设计治疗过程，利用新的动态平衡规则将整个系统重定向到正常的静息状态和对活动的正常反应模式。

DESCRIPTION (provided by applicant): Significance of this project resides in the magnitude and scope of Chronic Fatigue Syndrome (CFS) as a growing public health concern and in the inadequacy of current acute illness research models for resolving complex disorders affecting multiple regulatory systems in the body. This illness cuts across race, gender and socioeconomic status to affect a wide segment of society with costs to the US economy estimated at $9 billion in lost productivity and up to $24 billion dollars in health care expenditures annually. Moreover complications and co-morbidity can be severe, including cardiovascular illness and cancer, raising the stakes even further. Research has shown that immune, endocrine and nervous systems are all affected. Though these systems function in close collaboration CFS continues to be studied using a traditional piece-by-piece approach focusing on the failure of individual neuroendocrine and immune components. Hypothesis: We hypothesize that CFS results not only from component failure but perhaps more importantly from a significant deterioration of regulatory function linking these components. We will test regulatory fitness by using an exercise challenge to stimulate stress response and its modulation of the nervous, endocrine and immune systems. Objectives: The objective of this study is to improve our understanding of CFS pathogenesis in three ways: (i) by using broad-scale molecular profiling to create a comprehensive assessment of status in several of the body's regulatory systems, ii) by using information theory to integrate this disparate data into a single interpretable map describing the interactions between these physiologic systems and iii) by using novel elements of network theory to study the structure of these signaling networks and isolate alterations in the "wiring" that might be specific to CFS. Embedded in these maps we will also have captured the dynamic response of the overarching homeostatic control to exercise stress. This quantitative knowledge of the rates and directions with which biological information is disseminated through the neuroendocrine immune networks will be used as a basis for simulating response to treatment. Indeed computer simulations of neuroendocrineimmune response will be used to perform computer-aided design of candidate clinical trials in much the same way simulations have been used to train flight crews. By simulating CFS as an altered but stable control program treatment courses can be designed that exploit the new homeostatic rules to redirect the system as a whole to normal resting state and a normal pattern of response to activity.