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，“确定区分海湾战争疾病退伍军人和健康退伍军人的客观措施”，包括“利用新技术（蛋白质组学）的研究”。代谢组学方法）能够识别海湾战争疾病的独特分子特征，以及疾病和暴露亚组”是海湾战争研究的最高优先领域之一。 在本提案中，我们将通过使用最先进的“组学”技术（蛋白质组学、脂质组学和代谢组学）来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溴化吡啶斯的明）后的血浆分子，从而满足这一关键需求。我们将集中在GW-剂诱导的中枢神经系统（CNS）功能障碍的小鼠模型。将在不同的小鼠模型、不同的时间点和不同的临床表现中比较血浆谱，以鉴定与GW-药剂暴露后特异性调节的CNS功能障碍相关的生物学功能。与我们在波士顿和布朗克斯VA医院的临床合作者，我们将招募退伍军人与GWI，健康的GW退伍军人，和GW时代的退伍军人谁没有部署到海湾。我们将对他们的血浆进行类似的分析，并将比较临床亚组之间的谱，并使用小鼠研究的结果来鉴定对GWI CNS功能障碍最重要的差异性生物学功能。然后，我们将通过使用有针对性的“组学”调查和筛选额外的GW退伍军人人群来探索血浆生物标志物面板的开发，以通过确定正在调查的候选生物标志物的诊断特异性和灵敏度的再现性来鉴定发现阶段的生物标志物结果。 这一新颖的创新提案解决了许多与GWI相关问题相关的突出需求，a）诊断生物标志物，B）由于遗传异质性导致的生物反应差异，c）个性化医疗。还可以鉴定可用作评价治疗功效的替代物的生物标志物。此外，这项工作为现有和未来临床合作的其他样本的后续分析提供了模板。我们预计，我们的研究可以为海湾战争退伍军人疾病的全国性血浆生物标志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25%患有海湾战争病（GWI），其特征在于多症状表现，包括基于中枢神经系统（CNS）的症状，如认知缺陷、运动障碍和焦虑。GWI的诊断和临床管理的困难要求鉴定GWI临床亚组的有意义的外周生物标志物。现在已知诸如杀虫剂和杀虫剂的试剂参与GWI病因学，并且我们已经开发了在暴露于GW试剂后表现出CNS功能障碍的小鼠模型。在本申请中，我们建议使用我们最先进的蛋白质组学、脂质组学和代谢组学技术来开发用于诊断/管理GWI的生物标志物组。通过我们与GWI临床专家的合作，将我们的研究结果从GW-试剂诱导的CNS功能障碍的小鼠模型转化为明确的临床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.