Gender Differences in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

描述（由申请人提供）：肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）是一种复杂的疾病，涉及体内多个系统的持续失调，包括免疫系统、内分泌系统和心血管系统。这种情况对男女都有影响。然而，公布的队列显示女性占60%至80%的优势。为了了解功能障碍的潜在介质，我们的研究小组开发了一个动态模型来识别持续和复发的介质，其主要目标是确定疾病的潜在机制并更有效地靶向治疗。在这个应用程序中，我们转向性别差异。利用这个模型，包括对患者进行锻炼和多次抽血，以绘制基因组，细胞和化学反应的介质，我们建议比较ME/CFS的男性和女性。我们在相关海湾战争疾病（GWI）方面的研究已经证明了性别在调节功能障碍和反应方面的差异，这为本建议提供了一个现成和有用的比较组。虽然GWI和ME/CFS表现出相似的症状，但它们对运动的基因激活反应和不同的细胞因子特征截然不同，尽管它们具有共同的自主神经、炎症和细胞免疫功能障碍。重叠区域是有趣的潜在治疗靶点，尽管发现基于疾病（GWI vs. ME/CFS）和性别的截然不同的模型治疗策略并不奇怪。我们之前在男性GWI上的工作已经进展到1期临床试验，得到了新授予的国防部联盟资助。该联盟的目的是确定与男性患者GWI相关的信号机制，概述与这些信号通路相关的最有希望的生物标志物，以及干预研究的目标途径，这些研究不仅可以改善症状，还可以最终重置体内平衡。人们对这一方法的热情促使我们获得了资金，将这一方法应用到包括患有GWI的妇女的工作中。此外，我们还得到了NIH的资助，利用我们的动态模型评估ME/CFS女性患者和健康对照者在基因组、细胞和化学反应方面的差异。显然缺少的一环是对患有ME/CFS的男性进行比较，以进一步概述性别之间的反应差异，并为男性和女性制定有效的量身定制的治疗方法。我们还将扩展我们的免疫调节途径和调节潜伏病毒表达途径的建模工作，使我们能够在疾病机制方面比较性别差异，并探索性别特异性治疗靶点。我们的目标是了解ME/CFS男性患者持续和复发的因素，就像我们在女性患者中所做的那样。在此申请中，我们要求为ME/CFS患者的治疗目标/模型研究提供所需的资金，并要求深入进行有效的治疗。

DESCRIPTION (provided by applicant): Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition that involves persistent deregulation of multiple systems within the body including the immune, endocrine and cardiovascular systems. The condition affects both women and men. However, published cohorts indicate a 60 to 80% preponderance of women. In an effort to understand the underlying mediators of dysfunction, our research group has developed a dynamic model to identify the mediators of persistence and relapse, with the primary goal of pinpointing the underlying mechanisms of the condition and targeting treatment more effectively. In this application we turn to gender differences. Utilizing this model that involves challenging a patient with exercise and drawing bloods at multiple times to map out mediators of genomic, cellular and chemical response, we propose to compare men and women with ME/CFS. Our research efforts in the related gulf war illness (GWI) have demonstrated differences between gender in regulatory dysfunction and response that make a ready and useful comparison group for this proposal. While GWI and ME/CFS present with similar symptomatology, they have quite different gene activation responses to exercise and distinct cytokine signatures, though they share common autonomic, inflammatory and cellular immune dysfunction. Areas of overlap are intriguing potential therapeutic targets, though it would not be surprising to discover quite distinct modeled therapeutic strategies based on illness (GWI vs. ME/CFS) and gender. Our previous work in males with GWI has progressed to phase 1 clinical trials, as supported by a newly awarded DoD consortium grant. The aim of the consortium is to identify signaling mechanisms relevant to GWI in male patients and outline the most promising biomarkers tied to these signaling pathways and to target pathways for intervention studies that would not only improve symptomatology but ultimately reset homeostasis. The enthusiasm for this method has resulted in funding to move this to work to include women with GWI. In addition, we are also funded through the NIH to assess differences in genomic, cellular and chemical response using our dynamic model among female patients with ME/CFS and healthy controls. The clear missing link is the comparison of men with ME/CFS to outline further differences in response between genders and develop effective tailored treatments for both men and women. We will also extend our modeling work of immune regulatory pathways and pathways that regulate latent viral expression in a way that will enable us to compare gender differences in terms illness mechanisms and explore gender-specific therapeutic targets. We aim to understand the mediators of persistence and relapse in men with ME/CFS, as we have in women. We ask in this application for the funds needed for the therapeutic target/modeling studies of men with ME/CFS with the depth required to move toward effective therapy.