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.

这个试点GWI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。 我们以前已经开发并广泛表征了一种小鼠模型， 暴露于海湾战争制剂溴化吡斯的明（PB）和氯菊酯（PER） 其中所述小鼠接受急性（10天）暴露，然后在 时间点范围延伸至暴露后22个月（约2年） 年龄）。我们认为，这一模式与所遭受的相对急性暴露有关 1990年至1991年，我们的部队，和发展和持久的生殖医学 25年后。我们观察到神经行为缺陷和致病的生化和 这些小鼠的大脑和血液中的神经病理学变化。 衰老是一个影响大多数细胞、生物体和物种的生物学过程， 增加了对许多疾病包括神经变性疾病的易感性， 心血管疾病和癌症。端粒生物学现在被认为是一个关键的 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。GWI患者 患有各种各样的慢性病，我们假设他们的 与部署相关的暴露可能会导致端粒的根本性破坏， 生物稳态我们的细胞培养和动物模型的试验数据表明， 在暴露于GW剂PB后，存在端粒酶活性的破坏 的PER。 因此，本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GW-试剂暴露和未暴露小鼠队列的样品， 然后评估端粒酶维持/增强治疗的效果 化合物在GWI小鼠和对照的新队列中的作用。我们很感激 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代理如何引起这种中断的作用机制。但鉴于 我们目前的GWI患者群体在25年前遭受了毒性暴露， 我们希望首先在我们的模型中验证端粒/端粒酶破坏， 然后确定这一系列研究是否有希望作为治疗策略， 退伍军人与GWI。如果我们的假设成立，那么未来的全尺寸Merit提交 将探讨GW代理曝光和端粒生物学之间的关系， 更详细的信息来完善治疗方法。