Humanized Mouse Model of Gulf War Veterans' Illness

海湾战争退伍军人疾病的人源化小鼠模型

• 批准号: 10586598
• 负责人: Donald M Kuhn
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10586598
• 关键词: Animal Model; Anxiety; Award; Bromides; Chronic; Communicable Diseases; Communication; Complex; Development; Disease; Dose; Dyspepsia; Equation; Fatigue; Frequencies; Functional disorder; Gulf War; Gulf War veteran; Health; Heterogeneity; Human; Individual; Insecticides; Institute of Medicine (U.S.); Knowledge; Link; Literature; Minor; Modeling; Mus; Outcome; Pathologic; Patient Self-Report; Permethrin; Persian Gulf Syndrome; Phenotype; Pilot Projects; Post-Traumatic Stress Disorders; Psychophysiologic Disorders; Reporting; Sarin; Stretching; Study models; Symptoms; Testing; Toxicant exposure; Transplant Recipients; Uranium; Vaccines; War; anxiety-like behavior; associated symptom; blast exposure; burn pit; cohort; comorbidity; diagnostic criteria; disease mechanisms study; dysbiosis; fecal transplantation; gut microbiome; gut-brain axis; humanized mouse; imprint; innovation; learning outcome; microbiota transplantation; mouse model; pyridostigmine; sex; stool sample; stressor; toxicant

Gulf War Veterans' Illnesses (GWVI) is a complex constellation of symptoms that have persisted in Gulf War Veterans (GWV) more than 25 years after their deployment to the Gulf. These symptoms are so diverse, they baffle diagnostic criteria. As a result, consideration of GWVI as a bona fide illness has progressed slowly from denial of its existence to the use of such terms as “unexplained illnesses” (used by the VA) and “multisymptom illness”. The Institute of Medicine Committee on Gulf War and Health (2016) concludes that GWVI is not a psychosomatic condition and sufficient evidence now exists to conclude that a causal relationship exists between being deployed to the Gulf War and the health outcomes associated with this disorder. This Committee noted that little progress has been made in elucidating the pathological mechanisms that underlie the complex symptoms associated with GWVI and as a result, “it does not appear that a single mechanism can explain the multitude of symptoms seen in Gulf War Illness, and it is unlikely that a single definitive causal agent will be identified this many years after the war” (p. 3 of report). Another complexity relating to GWVI is establishing the toxicant exposure conditions to which GWVs were exposed. Potential agents include depleted uranium, pyridostigmine bromide (PB), sarin, vaccines, permethrin (PER) and other insecticide repellents, fuels, infectious diseases, stressors, burn pits and blast exposure. These potential toxicants form the basis for numerous animal models of GWVI. It is interesting that 3 of the major symptoms of GWVI- GI disruptions, PTSD/anxiety and chronic fatigue- can be caused individually by a dysbiosis in the gut microbiome, so it is reasonable to hypothesize that imbalances in the gut microbiome might contribute to these major 3 symptoms of GWVI collectively, and others as well. We (and others) have shown recently that PER/PB results in a significant alteration in the diversity and composition of the gut microbiome. Our animal model studies of GWVI-gut microbiome interactions are supported by a BLR&D Merit Award. A significant gap in the understanding of the pathophysiological underpinnings of GWVI arises from the lack of knowledge of the exact toxicant exposures. Self-reporting by GWVs is the basis of what is known about exposures, so it is hard to state with certainty, which agents (single, combinations) and their doses, frequencies and durations led to GWVI. This is an important point because we are learning that outcomes from animal model studies are dependent on the specific agent(s) used. One approach that could remove toxicant exposure conditions from the GWVI equation is the development of a humanized mouse model. In this manner, the GWVs toxicant exposures are already incorporated into the disorder along with its chronic, persistent symptomology. The objective of this Pilot Project is to develop a humanized mouse model via fecal microbiota transplantation (FMT) from stool samples of GWVs with GWVI into healthy mice. It is predicted that the gut microbiome of recipient mice will be colonized with that of the GWVI-donor and rapidly express the symptoms of this disorder. A humanized model of GWVI would incorporate the heterogeneity in symptomology observed in GWVI and maximize homogeneity in the cohorts of recipient mice. Studies of disease mechanisms, sex-based differences in symptomology and the testing of therapies not now possible in humans with GWVI would also become possible. These studies will also provide significant preliminary information to support a full Merit Review Award submission.

海湾战争退伍军人疾病（GWVI）是一个复杂的星座症状，一直持续在海湾战争 退伍军人（GWV）部署到海湾25年多后。这些症状是如此不同，他们 障碍诊断标准。因此，GWVI作为一种真正的疾病的考虑进展缓慢， 否认它的存在，以使用这样的术语，如“不明原因的疾病”（由退伍军人管理局使用）和“多症状” 病”。医学研究所海湾战争与健康委员会（2016）得出结论，GWVI不是一个 身心状况，现在有足够的证据得出结论，存在因果关系 被派往海湾战争和与这种疾病相关的健康结果之间的关系。这 委员会注意到，在阐明导致癌症的病理机制方面进展甚微， 与GWVI相关的复杂症状，因此，“似乎没有一种单一的机制可以 解释了海湾战争疾病中出现的众多症状，而且不太可能有一个明确的因果关系， 在战后这么多年，将查明代理人的身份”（报告第3页）。与GWVI相关的另一个复杂性是 确定GWVs所暴露的有毒物质暴露条件。潜在的代理人包括耗尽 铀、溴化吡啶斯的明、沙林、疫苗、氯菊酯和其他驱虫剂， 燃料、传染病、压力源、燃烧坑和爆炸暴露。这些潜在的有毒物质构成了 GWVI的许多动物模型。有趣的是，GWVI- GI中断的3个主要症状， 创伤后应激障碍/焦虑和慢性疲劳-可以单独由肠道微生物组的生态失调引起，所以它是 合理假设肠道微生物组的不平衡可能导致这3种主要症状 GWVI的集体，以及其他人。我们（和其他人）最近已经表明，PER/PB导致 肠道微生物组的多样性和组成发生显著变化。我们的动物模型研究 GWVI-肠道微生物组相互作用得到了BLR&D优异奖的支持。一个重大的差距， 对GWVI的病理生理基础的理解来自于缺乏对GWVI的确切机制的了解。 毒物暴露GWVs的自我报告是已知暴露的基础，因此很难 明确说明哪些药物（单药、复方制剂）及其剂量、频率和持续时间导致 GWVI.这一点很重要，因为我们了解到动物模型研究的结果是 这取决于所使用的特定试剂。一种可以消除有毒物质暴露条件的方法， GWVI方程是人源化小鼠模型的发展。以这种方式，GWVs有毒物质 暴露已经与其慢性、持续的病理学一起沿着于疾病中。的 本试验项目的目的是通过粪便微生物群移植开发人源化小鼠模型 (FMT)从具有GWVI的GWVs的粪便样品中分离到健康小鼠中。据预测， 受体小鼠将被GWVI-供体的受体定殖，并迅速表现出这种疾病的症状。 GWVI的人源化模型将结合在GWVI中观察到的组织学异质性， 最大化受体小鼠队列中的同质性。疾病机制研究，性别差异 目前在人类GWVI患者中不可能进行的治疗测试也将成为 可能这些研究还将提供重要的初步信息，以支持全面的实质审查 奖项提交。