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发病机理中的潜在作用。 我们以前已经开发并广泛表征了一个小鼠模型 暴露于海湾战争特工吡啶斯汀溴溴（PB）和苄氯菊酯（PER） 其中，小鼠会受到急性（10天）的暴露，然后在A处进行评估 暴露后22个月的时间点范围（大约2年 年龄）。我们认为该模型与相对急性暴露有关 由我们的部队在1990/1991，以及症状的发展和持久性 25年后。我们观察到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。 衰老是影响大多数细胞，生物和物种的生物学过程， 增加对包括神经退行性疾病在内的许多疾病的敏感性， 心血管疾病和癌症。端粒生物学现在是关键的 衰老和疾病过程的组成部分，呈现端粒维护 （通过端粒酶的作用）作为治疗靶标。患有GWI的人 患有各种各样的慢性疾病，我们假设他们 与部署相关的暴露可能导致端粒的根本中断 生物稳态。我们来自细胞培养和动物模型的飞行员数据表明 暴露于GW代理PB后，端粒酶活性会破坏 和per。 因此，该项目的目的是进一步探索血液中的这种现象 来自先前收集的GW代理暴露和未暴露的小鼠队列的样品， 然后评估端粒酶维持/增强治疗的影响 新的GWI小鼠和对照组中的化合物。我们感谢可能 端粒生物学在GWI中的作用提出了许多领域，以供进一步调查，包括 GW代理如何造成这种破坏的作用机制。但是，鉴于这一点 我们目前的GWI患者群体在25年前遭受了毒性暴露。 试点项目我们希望首先验证模型中的端粒/端粒酶破坏，并 然后确定此研究线是否有任何承诺作为治疗策略 与GWI的退伍军人。如果我们的假设得到了维持，那么将来的全尺度值得提交 将探索大部分GW代理暴露与端粒生物学之间的关系 更细节，以磨练治疗方法。