Omics and Variable Responses to Placebo and Acupuncture in Irritable Bowel Syndro

描述(申请人提供)：肠易激综合征(IBS)是一种慢性疾病，在工业化国家有10%-15%的人口受到影响。仅在美国，IBS就与患者生活质量的严重损害、生产力的显著损失以及20亿美元的直接医疗成本有关，这主要是由于治疗不令人满意。患者在疾病发病机制、症状表现和心理共病方面的异质性是导致治疗反应变化的因素之一。因此，需要开发生物标志物，以区分可能从特定治疗形式以及更重要的是从安慰剂治疗中受益最大的患者，这是当务之急。我们最近在IBS患者(n=262)中结束了一项为期6周的随机临床试验，以检查安慰剂和针灸治疗的效果，并与自然病史对照组进行比较。分别于基线、随访3周和6周采集血样。这项试验的积极结果和样本的可获得性使我们能够进行二级OMICS分析，检查患者对治疗的反应的变异性。我们的主要假设是血清蛋白直接或间接地参与了与IBS临床反应相关的脑-肠道相互作用。我们的第二个假设是，临床上对安慰剂或针灸治疗有反应的患者与那些没有反应的患者有不同的血清蛋白质谱。第三个假设是，安慰剂或针灸治疗会导致血清蛋白质组的变化。我们将结合各种高通量的实验方法，其中一些针对特定的生物路径，另一些导致公正的发现，以追求这项研究的目标。血清蛋白质组学分析将与对出现的感兴趣基因的常见多态进行调查相补充。这类研究的结果可能会改进基于生物筛选的随机临床试验中的纳入/排除标准。在个性化药物方面，研究结果可能导致增强药物反应、调整剂量或选择副作用较少的药物的方法。 公共卫生相关性：使用包括安慰剂效应在内的心理-身体机制进行自我康复可以对医疗保健产生重大影响，尽管对生物过程的定义和理解尚不明确。在之前由NIH资助的一项针对262名肠易激综合征(IBS)患者的临床研究中，我们表明，安慰剂治疗加上支持性的患者与医生之间的互动，可以显著改善这些患者的临床症状和整体生活质量。IBS是一种胃肠道疾病，影响了美国15%的人口。同一项研究还表明，针灸对一些患者有潜在的好处。目前的应用是对最初研究期间收集的血液样本进行二次后续分析。我们将使用高通量方法(OMICS)和生物信息学来确定安慰剂和针灸治疗的各种心身效应的生物标记。我们的第二个目标是产生一个生物特征，可以用来预测对这种非药物治疗有反应和没有反应的人。我们的研究结果将改进临床试验的设计，并为实践“个性化”医学做出贡献。

DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) is a chronic medical condition which affects 10-15% of the population in industrialized countries. IBS is associated with a profound impairment of patient's quality of life, significant loss of productivity, and $2 billion in direct health care costs in the US alone, mainly due to unsatisfactory treatment. Patient heterogeneity in terms of disease pathogenesis, symptom expression and psychological co-morbidities are among the factors implicated in the variation of therapeutic responses. Therefore, the need to develop biological markers that can distinguish patients likely to benefit most from specific forms of treatment, and as importantly, from a placebo treatment, is imperative. We have recently concluded a 6 week randomized clinical trial in IBS patients (n=262) to examine the effects of placebo and acupuncture treatments, compared to a natural history control group. Blood samples were collected at baseline and at 3 and 6 weeks of follow-up. The positive results of this trial and sample availability allow us to perform a secondary Omics analysis examining patient variability in response to treatment. Our primary hypothesis is that serum proteins participate directly or indirectly to the brain-gut interactions associated with clinical responses in IBS. Our second hypothesis is that patients who clinically respond to placebo or acupuncture treatment have distinct serum protein profiles from those who don't respond. A third hypothesis is that placebo or acupuncture treatment results in changes in the serum proteome. We will incorporate various high throughput experimental approaches, some of them targeted to specific biological pathways and others leading to unbiased discoveries, to pursue the goals of this study. The serum proteomics analysis will be complemented with an investigation of common polymorphisms in genes of interest that emerge. Findings stemmed from such studies could lead to improvement of inclusion/exclusion criteria in randomized clinical trials based on biological screens. In terms of personalized medicine, findings could result in methodologies to enhance medication responses, adjust the doses or select medications with fewer side effects. PUBLIC HEALTH RELEVANCE: Self healing using mind-body mechanisms, including placebo effects, can have a major impact on health care, though the biological process is poorly defined and understood. In a previous NIH-funded clinical study of 262 patients with irritable bowel syndrome (IBS), a gastrointestinal disease that affects up to 15% of the US population, we showed that placebo treatment, augmented by a supportive patient-practitioner interaction, could dramatically improve clinical symptoms and overall quality of life in those patients. The same study also indicated that acupuncture has potential benefit for some patients. The current application is a secondary, follow- up analysis of blood samples collected during the initial study. We will use high throughput approaches (Omics) and bioinformatics to identify biological markers for the various mind-body effects of placebo and acupuncture treatments. Our second goal is to generate a biological signature which can be used to predict individuals who respond and those who do not to such non-pharmacological treatments. Our findings will improve the design of clinical trials and contribute to the practice of "personalized" medicine.