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、内分泌和心血管系统。这种情况对女性和男性都有影响。然而，已公布的队列数据表明，妇女占60%至80%。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久性和复发的介质，其主要目标是查明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，涉及挑战患者运动和抽血多次映射出介导的基因组，细胞和化学反应，我们建议比较男性和女性ME/CFS。我们在相关的海湾战争疾病（GWI）的研究工作已经证明了性别之间的差异，在调节功能障碍和反应，使一个现成的和有用的比较组，这一建议。虽然GWI和ME/CFS表现出相似的运动学，但它们对运动的基因激活反应和不同的细胞因子特征非常不同，尽管它们具有共同的自主神经，炎症和细胞免疫功能障碍。重叠区域是有趣的潜在治疗靶点，尽管发现基于疾病（GWI与ME/CFS）和性别的完全不同的模型化治疗策略并不奇怪。我们之前在GWI男性中的工作已经进展到1期临床试验，得到了新授予的DoD财团资助的支持。该联盟的目的是确定男性患者中与GWI相关的信号传导机制，并概述与这些信号传导途径相关的最有前途的生物标志物，以及用于干预研究的靶向途径，这些研究不仅可以改善生殖学，而且最终可以重置稳态。对这种方法的热情导致了资金的投入，将其用于包括患有GWI的妇女。此外，我们还通过NIH获得资助，使用我们的动态模型评估ME/CFS女性患者和健康对照之间的基因组，细胞和化学反应差异。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，并探索性别特异性治疗靶点。我们的目标是了解ME/CFS男性的持久性和复发的介质，就像我们在女性中一样。我们在此申请中要求提供ME/CFS男性治疗靶点/建模研究所需的资金，其深度需要向有效治疗迈进。

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.