Identification of Plasma Biomarkers of Gulf War Illness Using "omic" Technology

描述(由申请人提供)： 海湾战争退伍军人疾病研究咨询委员会的最新报告指出，“确定客观的措施，区分患有海湾战争疾病的退伍军人和健康的退伍军人”，包括“利用能够识别海湾战争疾病、疾病和暴露亚群的独特分子特征的新技术(蛋白质组学……代谢方法)的研究”是海湾战争研究的最优先领域之一。在这项提案中，我们将通过使用最先进的“组学”技术(蛋白质组、脂组学和代谢组学)来解决这一关键需求，以全面表征小鼠暴露于海湾战争(GW)制剂(如杀虫剂和抗神经毒气剂吡斯的明溴)后的血浆分子。我们将重点介绍GW制剂诱导的中枢神经系统(CNS)功能障碍的小鼠模型。将比较不同小鼠模型、不同时间点和不同临床表现的血浆图谱，以确定与中枢神经系统功能障碍相关的生物学功能，这些功能在GW药剂暴露后受到特殊调节。与我们在波士顿和布朗克斯VA医院的临床合作者一起，我们将招募患有GWI的退伍军人、健康的GW退伍军人，以及没有部署到海湾地区的GW时代的退伍军人。我们将类似地描述他们的血浆，并将比较临床亚组之间的描述，并使用小鼠研究的结果来确定对GWI CNS功能障碍最重要的不同代表的生物学功能。然后，我们将探索血浆生物标记物小组的发展，通过使用有针对性的“基因组”调查，并筛选额外的GW退伍军人群体，通过确定正在研究的候选生物标记物的诊断特异性和敏感性的重复性，来鉴定发现阶段的生物标记物发现。这一新颖和创新的提案解决了与GWI相关问题的许多突出需求，a)诊断生物标记物，b)由于遗传异质性导致的生物反应差异，c)个性化药物。也可以确定生物标志物，这些生物标志物可以用作疗效评估的替代物。此外，这项工作为来自现有和未来临床合作的额外样本的后续分析提供了模板。我们期望我们的研究能够为海湾战争退伍军人疾病的全国性血浆生物标记物发现计划提供基础。 公共卫生相关性： 在1990-1991年海湾战争中服役的700,000名美国退伍军人中，约有25%患有海湾战争疾病(GWI)，其特征是表现为多症状，包括基于中枢神经系统(CNS)的症状，如认知障碍、运动障碍和焦虑。GWI的诊断和临床处理的困难要求确定GWI临床亚组的有意义的外周生物标志物。现在已知杀虫剂和杀虫剂等制剂与GWI病因学有关，我们一直在开发暴露于GW制剂后表现出中枢神经系统功能障碍的小鼠模型。在这项应用中，我们建议使用我们最先进的蛋白质组、脂组学和代谢组学技术来开发用于诊断/管理GWI的生物标志物小组。我们将通过与GWI临床专家的合作，将我们的研究结果从GW制剂诱导的中枢神经系统功能障碍的小鼠模型转化为明确定义的临床GW退伍军人群体，从而实现拟议的目标。

DESCRIPTION (provided by applicant): The most recent report from the Research Advisory Committee on Gulf War Veterans' Illnesses stated that "Identification of objective measures that distinguish Veterans with Gulf War Illness from Healthy Veterans" including "studies that utilize new technologies (proteomic...metabolomic methods) capable of identifying unique molecular characteristics of Gulf War Illness, and of illness and exposure subgroups" was one of the Highest Priority areas for Gulf War Research. In this proposal we will address this critical need by using state-of-the-art "omic" technology (proteomic, lipidomic and metabolomic) to comprehensively characterize plasma molecules responding to mouse exposure to Gulf War (GW) agents, such as pesticides and the anti-nerve gas agent pyridostigmine bromide. We will focus on mouse models of GW-agent induced central nervous system (CNS) dysfunction. Plasma profiles will be compared across different mouse models, different timepoints and different clinical presentations in order to identify biological functions correlating with CNS dysfunction that are specifically modulated following GW-agent exposure. With our clinical collaborators at the Boston and Bronx VA hospitals we will recruit Veterans with GWI, healthy GW Veterans, and GW-era Veterans who were not deployed to the Gulf. We will similarly profile their plasma, and will compare the profiles across clinical subgroups and use the results from the mouse studies to identify the differentially represented biological functions of most significance to GWI CNS dysfunction. We will then explore the development of a plasma biomarker panel by using targeted "omic" investigations and screening an additional GW Veterans population to qualify the biomarker findings from the discovery phase by determining the reproducibility of the diagnostic specificity and sensitivity of the candidate biomarkers under investigation. This novel and innovative proposal addresses many of the outstanding needs pertaining to issues related to GWI, a) diagnostic biomarkers, b) differences in biological responses due to genetic heterogeneity, c) personalized medicine. Biomarkers may also be identified which can be used as surrogates for evaluation of therapeutic efficacy. Furthermore, this work provides a template for subsequent analyses of additional samples from existing and future clinical collaborations. We anticipate that our study can provide the foundation for a nationwide plasma biomarker discovery program for Gulf War Veterans Illness. PUBLIC HEALTH RELEVANCE: Approximately 25% of the 700,000 US Veterans who served in the 1990-1991 Gulf War are afflicted with Gulf War Illness (GWI) which is characterized by a multisymptom presentation including central nervous system (CNS) based symptoms, such as cognitive deficits, motor impairment and anxiety. Difficulties in diagnosis and clinical management of GWI mandate identification of meaningful peripheral biomarkers of clinical subgroups of GWI. Agents such as pesticides and insecticides are now known to be involved in GWI etiology, and we have been developing mouse models that exhibit CNS dysfunction after exposure to GW- agents. In this application we propose to use our state-of-the-art proteomic, lipidomic and metabolomic technology to develop a biomarker panel for the diagnosis/management of GWI. The proposed objectives will be accomplished by translating our findings from the mouse models of GW-agent induced CNS dysfunction to well defined clinical GW Veterans populations, through our collaborations with clinical experts in GWI.