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

女性与男性 GWI：计算模型和治疗目标的差异

• 批准号: 9336857
• 负责人: Nancy Grace Klimas
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336857
• 关键词: Affect; Award; Biological; Biological Markers; Blood; Cardiovascular system; Cells; Chemicals; Chronic Fatigue Syndrome; Clinical; Clinical Trials; Complex; Computer Simulation; Cytokine Gene; Data; Data Set; Deterioration; Differential Equation; Disease; Endocrine system; Entropy; Equilibrium; Evaluation; Exercise; Failure; Female; Fibromyalgia; Flow Cytometry; Functional disorder; Funding; Gender; Gene Activation; Gene Expression; Genes; Genomics; Goals; Grant; Gulf War; Health; Homeostasis; Hormones; Immune; Immune system; Individual; Intervention; Intervention Studies; Knowledge; Leukocytes; Link; Maps; Measures; Mediating; Mediator of activation protein; Metabolic Pathway; Methods; Modeling; Molecular; Molecular Profiling; Nature; Neuropeptides; Neurosecretory Systems; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Phase I Clinical Trials; Physiological; Pilot Projects; Population; Relapse; Research; Rest; Sample Size; Sex Characteristics; Signal Pathway; Signal Transduction; Source; Study models; Surface; Syndrome; System; Therapeutic; Time; Uncertainty; United States National Institutes of Health; Veterans; Woman; Women' s Health; Work; base; cell type; cohort; comparison group; control theory; cytokine; design; differential expression; dosage; gender difference; improved; individualized medicine; male; men; network models; peripheral blood; predictive modeling; psychologic; public health relevance; response; symptomatology; targeted treatment; therapeutic target

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.

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（包括免疫、内分泌和心血管系统）的持续失调。这种情况似乎影响了部署到GW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生病。虽然男性和女性的治疗都涉及到泌尿系统疾病的管理，但对与这种疾病相关的潜在功能障碍仍然缺乏明确的认识。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。利用这种动态模型，包括挑战患者运动和多次抽血，以绘制出基因组，细胞和化学反应的介质，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力量分析数据，知道尽管男性和女性之间的临床相似性，但这种疾病在男性和女性中的介导方式不同，但我们无法对女性持续性疾病的介导因素进行建模，以确定治疗目标，因为我们在GWI男性中，完全是由于我们的样本量小。 我们之前在GWI男性中的工作已经进展到1期临床试验，这得到了新授予的DoD财团资助和提交的VA临床试验提案的支持。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。此外，我们还通过NIH资助，使用CFS/ME或纤维肌痛女性患者和健康对照组的动态模型评估基因组，细胞和化学反应的差异。随着这些研究的进行，我们正在更详细地了解与GWI相关的男性和女性相关疾病CFS/ME的关键代谢途径相关的功能障碍。明确缺失的环节是将女性与GWI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治疗方法。 在这项价值申请中，我们提出了一项“增值”研究，该研究结合了我们目前的研究工作，以彻底探索跨平台的性别差异，该平台能够评估GWI女性的基因组，细胞和化学反应介质，样本量足以支持组间比较和疾病修饰干预措施的建模。我们也有一个现有的动态数据集，在女性和男性慢性疲劳综合征（CFS/ME），一个有趣的比较组时，比较疾病模型。通过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，并探索性别特异性治疗靶点。通过利用这些信息，我们的目标是了解GWI女性的持久性和复发的介质，并将我们的研究工作扩展到基于动态建模和治疗靶点的临床试验，就像我们在男性中所做的那样。