Maintenance of telomerase activity as a treatment for Gulf War Illness

该GWI试验性研究项目旨在扩展和验证我们早期的发现 端粒生物学/端粒酶破坏在GWI发病机制中的潜在作用。 我们之前已经开发并广泛表征了一种小鼠模型 接触海湾战剂溴化吡斯的明(PB)和氯菊酯(PER) 其中小鼠接受急性(10天)暴露，然后在 持续到暴露后22个月的时间点范围(大约2年 年龄)。我们认为这一模型与相对急性的暴露有关。 我们部队在1990/1991年期间，以及症状学的发展和持续 25年后。我们观察神经行为缺陷和致病的生化和 这些小鼠大脑和血液中的神经病理变化。 衰老是一个影响大多数细胞、生物体和物种的生物过程， 对包括神经退行性疾病在内的许多疾病的易感性增加， 心血管疾病和癌症。端粒生物学现在被认为是一种关键 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导致端粒的根本性破坏 生物动态平衡。我们来自细胞培养和动物模型的试验数据表明 暴露于GW制剂PB后端粒酶活性被破坏 和PER。 因此，本项目的目标是进一步探索血液中的这种现象 来自先前收集的暴露于GW制剂的和未暴露的小鼠队列的样本， 然后评估端粒酶维持/增强治疗的效果 GWI小鼠和对照组新队列中的化合物。我们感谢这一可能的 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代理如何造成这种干扰的作用机制。然而，鉴于 我们现在的GWI患者在25年前遭受了他们的中毒暴露，在这个 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 有GWI的退伍军人。如果我们的假设成立，那么未来的全面提交 将探索GW制剂暴露与端粒生物学之间的关系 更多细节，以磨练治疗方法。

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.