Maintenance of telomerase activity as a treatment for Gulf War Illness

维持端粒酶活性作为海湾战争疾病的治疗方法

• 批准号: 9241532
• 负责人: FIONA C. CRAWFORD
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241532
• 关键词: 2 year old; Acute; Affect; Age; Aging; Animal Model; Area; Biochemical; Biological Process; Biology; Blood; Blood specimen; Brain; Bromides; Cardiovascular Diseases; Cell Aging; Cell Culture Techniques; Cell division; Cells; Chromosomes; Chronic; Clinical; Clinical Trials; Cognitive; Cognitive deficits; Conflict (Psychology); Data; Degenerative Disorder; Dermatologic; Dermatology; Development; Disease; Endocrine; Enzymes; Evaluation; Exhibits; Exposure to; Functional disorder; Future; Genomics; Goals; Gulf War; Health; Homeostasis; Individual; Inflammation; Insecta; Institutes; Investigation; Laboratories; Length; Maintenance; Malignant Neoplasms; Measures; Military Personnel; Modeling; Mus; Neuraxis; Neurodegenerative Disorders; Neurotoxins; Organism; Pathogenesis; Pathogenicity; Patients; Peripheral; Permethrin; Pilot Projects; Predisposition; Process; Prophylactic treatment; Proteomics; Reporting; Research; Research Project Grants; Role; Symptoms; Telomerase; Telomere Maintenance; Telomere Shortening; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxicant exposure; Veterans; Work; age related; base; chronic pain; cohort; effective therapy; experience; gastrointestinal; improved; lipid metabolism; mouse model; neurobehavioral; novel; patient population; persistent symptom; pyridostigmine; respiratory; symptomatology; targeted treatment; telomere; therapeutic target; treatment effect

This pilot GWI research project seeks to extend and validate our early findings of a potential role for telomere biology/telomerase disruption in GWI pathogenesis. We have previously developed and extensively characterized a mouse model of exposure to the Gulf War agents Pyridostigmine Bromide (PB) and Permethrin (PER) wherein the mice receive acute (10 days) exposure and have then been evaluated at a range of timepoints extending to 22 months post exposure (approximately 2 years of age). We consider that this model is relevant to the relatively acute exposure suffered by our troops in 1990/1991, and the development and persistence of symptomatology 25 years later. We observe neurobehavioral deficits and pathogenic biochemical and neuropathological changes in the brains and blood of these mice. Aging is a biological process that affects most cells, organisms and species, increasing susceptibility to many diseases including neurodegenerative diseases, cardiovascular disease and cancer. Telomere biology is now known to be a critical component of the aging and disease process, presenting telomere maintenance (through action of the telomerase enzyme) as a therapeutic target. Individuals with GWI suffer from a diverse array of chronic conditions, and we have hypothesized that their deployment related exposures may have caused a fundamental disruption of telomere biology homeostasis. Our pilot data from cell culture and our animal models suggest that there is disruption of telomerase activity following exposure to the GW agents PB and PER. Thus, the goal of this project is to further explore this phenomenon in blood samples from previously collected GW-agent-exposed and unexposed mouse cohorts, and to then evaluate the effects of treatment with telomerase maintaining/boosting compounds in new cohorts of GWI mice and controls. We appreciate that a possible role for telomere biology in GWI presents many areas for further investigation, including mechanism of action for how GW agents caused such disruption. However, given that our current GWI patient population suffered their toxic exposures 25 years ago, in this pilot project we wish to first validate telomere/telomerase disruption in our model, and then determine if this line of research holds any promise as a therapeutic strategy for veterans with GWI. If our hypothesis is upheld, then a future full scale Merit submission will explore the relationship between GW agent exposure and telomere biology in much greater detail, to hone therapeutic approaches.

该 GWI 试点研究项目旨在扩展和验证我们的早期发现 端粒生物学/端粒酶破坏在 GWI 发病机制中的潜在作用。 我们之前开发并广泛表征了小鼠模型 接触海湾战争制剂溴吡斯的明 (PB) 和氯菊酯 (PER) 其中小鼠接受急性（10天）暴露，然后在 时间点范围延伸至暴露后 22 个月（大约 2 年） 年龄）。我们认为该模型与所遭受的相对严重的暴露有关 1990/1991 年我们部队发生的疾病，以及症状的发展和持续 25年后。我们观察神经行为缺陷和致病性生化和 这些小鼠的大脑和血液的神经病理学变化。 衰老是一个影响大多数细胞、生物体和物种的生物过程， 增加对许多疾病的易感性，包括神经退行性疾病， 心血管疾病和癌症。现在已知端粒生物学是一个关键 衰老和疾病过程的组成部分，呈现端粒维持 （通过端粒酶的作用）作为治疗靶点。患有 GWI 的个人 患有多种慢性病，我们假设他们 与部署相关的暴露可能导致端粒的根本性破坏 生物学稳态。我们的细胞培养试验数据和动物模型表明 接触 GW 制剂 PB 后端粒酶活性会受到破坏 和每。 因此，该项目的目标是进一步探索血液中的这种现象 来自先前收集的暴露于 GW 剂和未暴露于 GW 剂的小鼠群体的样本， 然后评估端粒酶维持/增强治疗的效果 在新的 GWI 小鼠组和对照小鼠中研究化合物。我们赞赏可能的 端粒生物学在 GWI 中的作用提出了许多需要进一步研究的领域，包括 GW 代理如何造成这种破坏的作用机制。然而，鉴于 我们当前的 GWI 患者群体在 25 年前就遭受了有毒物质暴露，在这 我们希望首先在我们的模型中验证端粒/端粒酶破坏的试点项目，以及 然后确定这一系列研究是否有希望作为治疗策略 具有 GWI 的退伍军人。如果我们的假设成立，那么未来将全面提交优点 将在很多方面探讨 GW 剂暴露与端粒生物学之间的关系 更详细的内容，以磨练治疗方法。