Bridging animal and human models of exercise-induced visual rehabilitation

连接运动引起的视觉康复的动物和人类模型

• 批准号: 8924254
• 负责人: JEFFREY H BOATRIGHT
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8924254
• 关键词: Activities of Daily Living; Adherence; Adjuvant; Aerobic Exercise; Affect; Age related macular degeneration; Aging; Animals; Bicycling; Biological Markers; Blindness; Blood; Brain-Derived Neurotrophic Factor; Caring; Clinic; Cognition; Cognitive; Collection; Contrast Sensitivity; Data; Diabetic Retinopathy; Disease; Disease Progression; Dose; Electroretinography; Enrollment; Exercise; Exercise stress test; Feasibility Studies; Frequencies; Funding; General Population; Glaucoma; Goals; Health; High Prevalence; Hippocampus (Brain); Human; International; Intervention; Light; Measures; Mediating; Mission; Modeling; Morphology; Mus; Nervous System Physiology; Neuraxis; Neurocognitive; Neurodegenerative Disorders; Operative Surgical Procedures; Optical Coherence Tomography; Outcome; Parkinson Disease; Patients; Peripheral; Peripheral Nervous System; Pharmacological Treatment; Physical activity; Physical therapy exercises; Population; Prevalence; Regimen; Rehabilitation therapy; Research Personnel; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Rodent; Running; Self-control as a personality trait; Serum; Signal Transduction; Structure; Testing; Time; Training; Training Programs; Translating; Treatment Cost; Veterans; Vision; Visual; Visual Acuity; Visual impairment; Work; aged; base; cost; cost effective; dosage; effective therapy; healthy aging; human subject; improved; in vivo; inhibitor/antagonist; intervention effect; neuroprotection; prevent; programs; protective effect; public health relevance; research and development; retinal neuron

 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.

 描述（由申请人提供）： 亚特兰大VA视觉和神经认知康复卓越中心（CVNR）的研究人员发现，老年退伍军人中致盲疾病的患病率非常高。几乎没有治疗威胁我们退伍军人视力的疾病的方法。我们的总体目标是开发低成本的治疗方法，以减缓健康老龄化或视网膜疾病引起的渐进性视力丧失。这里提出的工作是确定老年退伍军人是否可以使用运动作为视力丧失的廉价和自我控制的治疗方法的第一步。检测干预对人类受试者的影响可能需要几年或几十年。为了将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志物。虽然人类和动物研究表明，有氧运动有益于特定的中枢和外周神经系统功能，但对视网膜和视力的影响是未知的，直到我们最近发现跑步机运动直接保护经历光诱导视网膜变性（LIRD）的小鼠的视网膜神经元。此外，我们发现，运动增加血清，海马和视网膜中的脑源性神经营养因子（BDNF）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，我们的工作在国内和国际媒体上引起了兴奋，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周的自行车旋转运动方案，可显著改善健康老年人和帕金森病患者的认知能力。坚持率非常高（超过90%），这表明这是一种可靠的方法来改变退伍军人的有益活动。我们的研究和其他人的研究表明，循环营养因子随运动方案的变化而变化，因此可以用作运动神经保护作用的潜在生物标志物。例如，在小鼠和人类中增加体力活动会增加循环BDNF并促进有益的结果。然而，目前尚不清楚循环BDNF水平是否与视力结果相关，并可用作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增加血清BDNF水平并改善经历LIRD的小鼠的视网膜保护。结果将包括视网膜电图（ERG）评估的视网膜功能和视动追踪（OKT）和BDNF水平评估的敏锐度和对比敏感度。将通过光学相干断层扫描（OCT）评估体内形态。在目标2中，我们将评估人类受试者在有氧运动之前，期间和之后的视觉结果和血清BDNF。目前参加为期12周的CVNR研究的受试者将进行视力测试，该研究旨在检查有氧运动对认知的影响（ERG、视敏度、对比敏感度和OCT）和采血，在我们的标准化12周有氧运动方案期间和之后，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Aim 1动物研究中预测的那样改变。这项研究将确定生物标志物的可行性 来预测运动对视力的保护作用。与手术或药物治疗相反，锻炼计划为退伍军人提供了一种控制视力疾病进展的手段，并将提高他们的整体健康水平。一旦确定了适当的生物标志物，我们将提交一份Merit提案，以确定视力受损受试者运动的益处。