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，老年退伍军人人口中盲目疾病的患病率很高。对于威胁我们退伍军人视力的疾病的治疗很少。我们的总体目标是开发低成本治疗，以缓慢的健康衰老或残留疾病引起的渐进视力丧失。这里提出的工作是确定老年退伍军人是否可以将运动用作廉价且自我控制的疗法，以供视力丧失使用。检测干预对人类受试者的影响可能需要数年或几十年。为了将运动疗法转化为诊所，我们需要确定可用于预测视觉益处的生物标志物。尽管人类和动物的研究表明，有氧运动对特定的中枢和周围神经系统的功能有益，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了感光诱发的视网膜变性的小鼠中的视网膜神经元（lird）。此外，我们发现运动在血清，海马和视网膜中锻炼脑衍生的神经营养因子（BDNF）水平增加，而用BDNF抑制剂对小鼠进行治疗阻止了运动的受保护作用。由于老出的模型模仿了包括AMD在内的人类视网膜疾病的几个方面，因此我们的工作在国家和国际出版社中引起了兴奋，在该媒体上进行了讨论，作为一种潜在的与衰老有关的盲目疾病的疗法。另外，在三项VA资助的研究中，我们开发了一个为期12周的自行车旋转运动方案，可显着改善健康老年人和帕金森病患者的认知。依从性很高（超过90％），这表明这是改变对退伍军人有益活动的可靠方法。我们的研究和其他研究表明，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，小鼠和人类的体育活动增加增加了循环的BDNF并促进有益的结果。但是，尚不清楚循环BDNF水平是否与视觉结果相关，并且可以用作缓慢发展的视网膜疾病的预测生物标志物。我们假设优化的运动方案以增加循环的BDNF将提供最佳的结果。在AIM 1中，我们将测试改变跑步机运动方案是否会增加血清BDNF的水平并改善小鼠的视网膜保护。结果将包括通过电子图（ERG）评估的视网膜功能以及通过光疗跟踪（OKT）和BDNF水平评估的敏锐度以及对比度灵敏度。体内形态将通过光学相干断层扫描（OCT）评估。在AIM 2中，我们将在有氧运动之前，期间和之后评估人类受试者的视觉结果和血清BDNF。目前正在参加为期12周的CVNR研究的受试者研究有氧运动对认知的影响将进行视觉测试（ERG，视力，敏锐度，对比度以及OCT敏感性以及OCT）和血液收集和血液收集，然后在我们标准化的12周有氧运动锻炼方案中和之后，我们的bdnf级别和视觉量是否适用于BDNF级别和视觉级别是否适用于BDNF级别，并确定该级别是否对BDNF进行了研究。生物标志物的可行性 预测锻炼的视力益处。与手术或药物治疗相反，锻炼计划为退伍军人提供了一种对视觉疾病进展的控制权并将提高整体健康状况的方法。一旦确定了适当的生物标志物，我们将提交一项优点建议，以确定在视觉受损的受试者中锻炼的好处。