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，涉及体内包括免疫、内分泌和心血管系统在内的多种系统的持续放松调节。这种情况似乎对被部署到GW的男性和女性都有影响，这些受影响的退伍军人中多达三分之一至今仍在患病。虽然男性和女性的治疗都涉及到症状的处理，但对与这种情况相关的潜在功能障碍仍然缺乏明确的了解。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这些持续和复发的媒介，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。利用这个动态模型，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，我们研究了50名男性和10名女性GWI疾病。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媒介是不同的，尽管男女在临床上有相似之处，但我们还无法对女性持续性疾病的介体进行建模，以确定治疗靶点，完全是因为我们的样本量很小。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，这得到了新授予的国防部联盟拨款和提交的VA临床试验提案的支持。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。此外，我们还通过美国国立卫生研究院提供资金，使用动态模型评估患有CFS/ME或纤维肌痛的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。随着这些研究的进行，我们正在更详细地了解男性和患有相关疾病CFS/ME的女性GWI中涉及的关键代谢途径相关的功能障碍。明显缺失的一环是将女性与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量身定制的治疗方法。在这项优点申请中，我们提出了一项“增值”研究，该研究结合了我们目前的研究努力，在一个平台上彻底探索性别差异，从而能够使用足够大的样本量来评估患有GWI的女性的基因组、细胞和化学反应介质，以支持组间比较和疾病改善干预的建模。我们也有一个现有的慢性疲劳综合征(CFS/ME)女性和男性的动态数据集，在比较疾病模型时，这是一个有趣的比较组。有了现有的数据和增强的女性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GWI女性患者持续和复发的中介因素，并将我们的研究努力扩展到基于动态建模和治疗目标的临床试验，就像我们在男性身上所做的那样。

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.