Gender Differences in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

描述(申请人提供)：肌痛性脑脊髓炎/慢性疲劳综合症(ME/CFS)是一种复杂的疾病，包括免疫、内分泌和心血管系统在内的体内多个系统持续放松调节。这种情况对女性和男性都有影响。然而，公布的队列显示，女性占60%至80%。为了了解功能障碍的潜在媒介，我们的研究小组开发了一个动态模型来确定持续性和复发的媒介，主要目标是查明疾病的潜在机制，并更有效地进行靶向治疗。在这个应用程序中，我们转向性别差异。利用这一模型，包括通过锻炼挑战患者并多次抽血来绘制基因组、细胞和化学反应的中介，我们建议将男性和女性与ME/CFS进行比较。我们对相关的海湾战争疾病(GWI)的研究工作表明，在调节功能障碍和反应方面存在性别差异，这为这一提议提供了一个现成和有用的对比小组。虽然GWI和ME/CFS具有相似的症状，但它们对运动的基因激活反应和不同的细胞因子信号非常不同，尽管它们具有共同的自主神经、炎症和细胞免疫功能障碍。重叠的领域是耐人寻味的潜在治疗目标，尽管根据疾病(GWI与ME/CFS)和性别发现截然不同的建模治疗策略并不令人惊讶。我们之前在患有GWI的男性患者中的工作已经进展到第一阶段临床试验，这是由新授予的国防部财团拨款支持的。该联盟的目的是确定与男性患者GWI相关的信号机制，并概述与这些信号通路相关的最有前途的生物标记物，并针对干预研究的通路，不仅改善症状，而且最终重置内环境平衡。对这种方法的热情导致了将其转移到工作中的资金，以包括患有GWI的妇女。此外，我们还通过美国国立卫生研究院提供资金，使用我们的动态模型评估ME/CFS女性患者和健康对照组在基因组、细胞和化学反应方面的差异。明显缺失的环节是将男性与ME/CFS进行比较，以概述性别之间反应的进一步差异，并为男性和女性开发有效的量身定制的治疗方法。我们还将扩展免疫调节途径和调节潜伏病毒表达的途径的建模工作，使我们能够比较疾病机制方面的性别差异，并探索针对性别的治疗靶点。我们的目标是了解男性ME/CFS患者持续和复发的中介因素，就像我们在女性患者中所做的那样。在这份申请中，我们要求提供用于ME/CFS患者的治疗目标/模型研究所需的资金，这些研究具有迈向有效治疗所需的深度。

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.