Women v Men with GWI: Differences in Computational Models and Therapeutic Targets

描述（由申请人提供）： 海湾战争病 (GWI) 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。这种情况似乎影响到被部署到乔治城的男性和女性，其中多达三分之一的受影响退伍军人今天仍然患病。虽然男性和女性的治疗都涉及症状管理，但对与这种情况相关的潜在功能障碍仍然缺乏清晰的了解。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这些持续性和复发的介质，其主要目标是查明该疾病的潜在机制并更有效地进行针对性治疗。在此应用程序中，我们转向性别差异。利用这种动态模型，包括对患者进行多次运动和抽血，以找出基因组、细胞和化学反应的介质，我们研究了 50 名患有 GWI 疾病的男性和 10 名女性。虽然我们已经能够以足够的能力分析数据，知道这种疾病在男性和女性中的介导方式不同，尽管两种性别之间存在临床相似性，但我们无法对女性持续性疾病的介导因素进行建模，以达到像男性 GWI 那样确定治疗靶点的程度，这完全是由于我们的样本量较小。 在新授予的国防部财团拨款和提交的 VA 临床试验提案的支持下，我们之前针对 GWI 男性的工作已进展到一期临床试验。该联盟的目标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希望的生物标志物，并确定干预研究的目标途径，这些干预研究不仅可以改善症状，而且最终可以重置体内平衡。此外，我们还通过 NIH 获得资助，利用动态模型评估患有 CFS/ME 或纤维肌痛的女性患者与健康对照者在基因组、细胞和化学反应方面的差异。随着这些研究的进行，我们正在更详细地了解患有相关疾病（CFS/ME）的男性和女性中与 GWI 相关的关键代谢途径相关的功能障碍。明显缺失的环节是将女性与 GWI 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定制治疗方法。 在此优点申请中，我们提出了一项“增值”研究，该研究结合了我们当前的研究工作，旨在通过一个平台彻底探索性别差异，该平台能够使用足以支持组间比较和疾病缓解干预建模的样本量来评估 GWI 女性的基因组、细胞和化学反应介质。我们还有一个现有的慢性疲劳综合症 (CFS/ME) 女性和男性动态数据集，这是比较疾病模型时有趣的比较组。借助现有数据和增强的女性 GWI 队列，我们​​将能够比较疾病、疾病机制方面的性别差异，并探索针对性别的治疗目标。通过利用这些信息，我们的目标是了解女性 GWI 持续存在和复发的调节因素，并将我们的研究工作扩展到基于动态模型和治疗目标的临床试验，就像我们在男性中所做的那样。

DESCRIPTION (provided by applicant): Gulf War Illness (GWI) is a complex condition that involves persistent deregulation of multiple systems within the body including the immune, endocrine, and cardiovascular systems. The condition appears to affect both men and women who were deployed to the GW, with up to one-third of these affected Veterans remaining ill today. While treatment of both men and women has involved management of symptomatology, a lack of clear understanding of the underlying dysfunction associated with this condition remains. In an effort to understand the underlying mediators of dysfunction, our research group has developed a dynamic model to identify these 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 dynamic 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 have studied 50 men and 10 women with GWI illness. While we have been able to analyze the data with enough power to know that the disease is mediated differently in men and women despite clinical similarities between the two genders, we have not been able to model the mediators of persistent illness in women to the point of identifying therapeutic targets as we have in men with GWI, entirely due to our small sample size. Our previous work in males with GWI has progressed to Phase 1 clinical trials, as supported by a newly awarded DoD consortium grant and a submitted VA clinical trials proposal. 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. In addition, we are also funded through the NIH to assess differences in genomic, cellular, and chemical response using a dynamic model among female patients with CFS/ME or fibromyalgia and healthy controls. With these studies underway, we are developing a more detailed understanding of the dysfunction associated with key metabolic pathways involved in GWI in men and in women with a related illness, CFS/ME. The clear missing link is the comparison of women with GWI to outline further differences in response between genders and develop effective tailored treatments for both men and women. In this merit application, we propose a "value added" study that incorporates our current research efforts to thoroughly explore sex differences across a platform that enables evaluation of genomic, cellular, and chemical response mediators in women with GWI using a sample size sufficient to support between-group comparisons and modeling of illness-modifying interventions. We also have an existing dynamic data set in women and men with chronic fatigue syndrome (CFS/ME), an interesting comparator group when comparing illness models. With existing data and the enhanced female GWI cohort we will be able to compare gender differences in terms of illness, illness mechanisms, and explore gender-specific therapeutic targets. By utilizing this information, we aim to understand the mediators of persistence and relapse in women with GWI and extend our research efforts to clinical trials based on dynamic modeling and therapeutic targets, as we have in men.