Bridging animal and human models of exercise-induced visual rehabilitation

 描述(由申请人提供)： 亚特兰大弗吉尼亚州视觉和神经认知康复卓越中心(CVNR)的研究人员发现，在老年退伍军人中，致盲疾病的患病率非常高。对于威胁我们退伍军人视力的疾病，几乎没有治疗方法。我们的总体目标是开发低成本的治疗方法，减缓健康老龄化或视网膜疾病引起的进行性视力丧失。这里提出的这项工作是确定运动是否可以被老年退伍军人用作一种廉价的自我控制视力丧失疗法的第一步。检测干预对人类受试者的影响可能需要几年或几十年的时间。为了将视觉运动疗法应用于临床，我们需要确定可用于预测视觉益处的生物标记物。虽然人类和动物的研究表明有氧运动有利于特定的中枢和周围神经系统功能，但对视网膜和视力的影响尚不清楚，直到我们最近发现跑步机运动直接保护光致视网膜变性(LIRD)小鼠的视网膜神经元。此外，我们发现，运动增加了血清、海马体和视网膜中脑源性神经营养因子(BDNF)的水平，而用BDNF抑制剂治疗小鼠则阻止了运动的保护作用。由于Lird模型模拟了包括AMD在内的人类视网膜疾病的几个方面，我们的工作引起了国内和国际媒体的兴奋，在那里它被讨论为与衰老相关的致盲疾病的潜在疗法。另外，在VA资助的三项研究中，我们开发了一种为期12周的自行车旋转锻炼方案，显著改善了健康老年人和帕金森氏病患者的认知能力。依从性非常高(超过90%)，这表明这是改变退伍军人有益活动的可靠方法。我们和其他人的研究表明，循环营养因子随着运动方案的变化而变化，因此可能被用作运动神经保护效应的潜在生物标记物。例如，老鼠和人类的体力活动增加都会增加循环中的BDNF，并促进有益的结果。然而，目前尚不清楚循环中的BDNF水平是否与视力结果相关，是否可以作为缓慢进展的视网膜疾病的预测生物标志物。我们假设，优化运动方案以增加循环BDNF将提供最好的结果。在目标1中，我们将测试不同的跑步机运动方案是否会增加接受Lird的小鼠的血清BDNF水平，并改善其视网膜保护。结果将包括通过视网膜电图(ERG)评估视网膜功能，通过视动跟踪(OKT)和BDNF水平评估视力和对比敏感度。体内的形态将通过光学相干断层扫描(OCT)进行评估。在目标2中，我们将评估受试者在有氧运动之前、期间和之后的视觉结果和血清BDNF。目前正在参加一项为期12周的有氧运动对认知影响的CVNR研究的受试者将在标准化的12周有氧运动方案之前、期间和之后进行视觉测试(ERG、视力、对比敏感度和OCT)和采血，以确定循环BDNF水平和视觉结果是否相关，以及BDNF水平是否如目标1所预测的那样发生改变。这项研究将确定生物标记物的可行性 来预测运动对视力的保护作用。与手术或药物治疗不同，锻炼计划为退伍军人提供了一种手段，可以在一定程度上控制他们的视力疾病进展，并将改善他们的整体健康状况。一旦确定了合适的生物标记物，我们将提交一份功绩提案，以确定运动对视力受损对象的好处。

 DESCRIPTION (provided by applicant): Investigators of the Atlanta VA Center of Excellence for Visual and Neurocognitive Rehabilitation (CVNR) find a very high prevalence of blinding diseases in the aging veteran population. There are few treatments for the disorders that threaten our Veterans' eyesight. Our overall goal is to develop low-cost treatments that slow progressive vision loss in healthy aging or due to retinal diseases. The work proposed here is the first step in determining whether exercise can be used by aging Veterans as an inexpensive and self-controlled therapy for vision loss. Detecting the effects of an intervention on human subjects may take several years or decades. In order to translate exercise therapy for vision into the clinic, we need to identify biomarkers that can be used to predict visual benefits. Though human and animal studies show that aerobic exercise is beneficial to specific central and peripheral nervous system functions, effects on the retina and vision were unknown until we recently discovered that treadmill exercise directly protects retinal neurons in mice undergoing light-induced retinal degeneration (LIRD). In addition, we found that exercise increased levels of brain-derived neurotrophic factor (BDNF) in serum, hippocampus, and retina whereas treatment of mice with a BDNF inhibitor prevented the protective effects of exercise. Because the LIRD model mimics several aspects of human retinal diseases, including AMD, our work generated excitement in the national and international press, where it was discussed as a potential therapy for blinding diseases related to aging. Separately, in three VA-funded studies, we developed a 12-week bicycle spin exercise regimen that significantly improves cognition in healthy aged humans and in Parkinson's Disease patients. Adherence is very high (over 90%), suggesting that this is a reliable approach to altering beneficial activity for Veterans. Our studies and those of others suggest that circulating trophic factors vary with changes in exercise regimens and therefore may be used as a potential biomarker for the neuroprotective effects of exercise. For instance, increased physical activity in both mice and humans increases circulating BDNF and promotes beneficial outcomes. However, it is unknown whether circulating BDNF levels correlate with visual outcomes and could be used as a predictive biomarker in slowly progressing retinal diseases. We hypothesize that optimizing exercise regimens to increase circulating BDNF will provide the best outcomes. In Aim 1 we will test whether varying treadmill exercise regimens increase levels of serum BDNF and improve the retinal protection of mice undergoing LIRD. Outcomes will include retinal function assessed by electroretinogram (ERG) and acuity and contrast sensitivity assessed by optokinetic tracking (OKT) and BDNF levels. In vivo morphology will be assessed by optical coherence tomography (OCT). In Aim 2 we will assess visual outcomes and serum BDNF in human subjects before, during, and after aerobic exercise. Subjects currently enrolled in a 12-week CVNR study examining the effects of aerobic exercise on cognition will have visual testing (ERG, visual acuity, contrast sensitivity, and OCT) and blood collection prior to, during and after our standardized 12-week aerobic exercise regimen to determine whether circulating BDNF levels and visual outcomes are correlated and whether BDNF levels are altered as predicted in the animal studies from Aim 1. This study will determine the feasibility of biomarkers to predict sight-saving benefits of exercise. As opposed to surgery or pharmacological treatments, exercise programs provide a means for veterans to exert some control over their visual disease progression and will increase their overall health. Once the appropriate biomarkers are determined, we will submit a Merit proposal to determine the benefits of exercise in visually impaired subjects.