Laser speckle flowgraphy as early indicator of microvasculopathy in radiation-induced vision loss

激光散斑血流成像作为辐射引起的视力丧失中微血管病变的早期指标

基本信息

批准号：
10615636
负责人：
Isabella Maria Grumbach
金额：
$ 48.95万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615636
关键词：
Adult Aftercare Angiography Animal Model Blindness Blood Vessels Blood capillaries Blood flow Brachytherapy Choroid Melanoma Data Development Dropout Early Diagnosis Early identification Endothelial Cells Endothelium Eye Eye diseases Funding Future Genetic Goals Human Image Impairment Infusion procedures Injury Knowledge Lasers Light Lung Malignant Neoplasms Measurement Measures Mediator Methods Mission Mitochondria Modality Molecular Mus Non-Invasive Detection Ocular Melanoma Optical Coherence Tomography Organ Outcome Oxidative Stress Pathology Patients Perimetry Pilot Projects Prevention Production Prospective cohort Protocols documentation Public Health Radiation Reactive Oxygen Species Reporting Research Research Support Retina Retinal Diseases Role Severities Structure Superoxides Testing Tissues United States National Institutes of Health Uveal Melanoma Vascular Diseases Vascular Endothelium Vasodilation Vision Visual Acuity Visual impairment choroidal circulation cohort density early detection biomarkers endothelial dysfunction experience human data human subject in vivo insight melanoma mitochondrial dysfunction mouse model novel novel therapeutics overexpression prevent programs prospective radiation-induced injury real-time images response retina circulation retinal damage standard care targeted treatment vascular endothelial dysfunction

项目摘要

PROJECT SUMMARY/ABSTRACT At least 50% of patients treated with 125I brachytherapy for uveal melanoma experience significant vision loss within 3-5 years after therapy. Extensive vascular pathology has been reported in the normal retina surrounding the melanoma after 2 years or more. These findings are in line with the accepted, but incompletely tested, concept that microangiopathy causes radiation-related vision loss due to injury of the microvascular endothelium during radiation. This leads to progressive capillary loss after a lag period of several years. If this hypothesis is correct, preventing the development of, or treating, radiation-induced endothelial damage in retinal microvessels will reduce capillary loss and save vision. However, this approach has been difficult to test because early indicators of microvascular endothelial dysfunction have yet to be established. The objectives of the proposed project are to: facilitate earlier detection, treatment and prevention of radiation- associated vision loss. Specifically, we expect to 1. detect early endothelial dysfunction based on reduced blood flow and response to light flicker 2. determine whether it is predictive of subsequent capillary loss and 3. identify molecular mechanisms of radiation-induced endothelial dysfunction. We will apply laser speckle flowgraphy (LSFG) for noninvasive, real-time imaging and measurement of ocular blood flow, in human subjects and mice to test our central hypothesis, that post-radiation endothelial dysfunction is driven by mitochondrial oxidative stress, and is predictive of the severity of subsequent capillary dropout and vision loss. We will test our hypothesis in two aims: Aim 1: Establish whether early impairment of the microvascular endothelial function will predict microvessel drop-out and vision loss in humans after 125I brachytherapy. For this purpose, LSFG, optical coherence tomography (OCT) and OCT-angiography (OCT-A) and tests of visual function will be performed in a prospective cohort of patients undergoing 125I brachytherapy for choroidal melanoma. We will test whether early impairment of ocular blood flow and flicker light-induced vasodilation by LSFG correlate with subsequent vision loss and capillary drop-out (as detected by OCT-A). Aim 2: Test whether selective inhibition of mitoROS production in endothelium prevents the early reduction of blood flow and subsequent loss of capillaries after radiation. In this aim, genetic mouse models in which key regulators of mitochondrial superoxide production are inhibited or overexpressed will be used to test whether inhibition of mitochondrial ROS in the endothelium protects from early impairment of retinal blood flow, endothelial dysfunction and subsequent capillary dropout. The expected outcomes of the proposed studies are knowledge of biomarkers of early radiation retinopathy and insights into the role of endothelial-cell mitochondrial dysfunction in radiation retinopathy. Our studies have the potential to facilitate the development of first-in-class, targeted therapies for radiation-related vision loss.

项目概要/摘要接受 125I 近距离放射治疗葡萄膜黑色素瘤的患者中，至少 50% 出现严重视力丧失治疗后3-5年内。据报道，正常视网膜存在广泛的血管病理学 2年或更长时间后黑色素瘤周围。这些发现与公认的一致，但不完全一致经过测试的概念是，微血管病变会因微血管损伤而导致与辐射相关的视力丧失辐射期间的内皮细胞。这导致在几年的滞后期后进行性毛细血管损失。如果这个假设是正确的，可以预防或治疗辐射引起的内皮损伤视网膜微血管将减少毛细血管损失并挽救视力。然而，这种方法很难测试因为微血管内皮功能障碍的早期指标尚未确定。拟议项目的目标是：促进辐射的早期检测、治疗和预防相关的视力丧失。具体来说，我们期望 1. 基于减少的内皮功能障碍检测早期内皮功能障碍。血流和对光闪烁的反应 2. 确定它是否可以预测随后的毛细血管损失 3. 确定辐射引起的内皮功能障碍的分子机制。我们将应用激光散斑血流成像 (LSFG) 用于人体眼部血流的无创实时成像和测量受试者和小鼠来测试我们的中心假设，即辐射后内皮功能障碍是由线粒体氧化应激，并可预测随后毛细血管脱落的严重程度视力丧失。我们将在两个目标上检验我们的假设：目标 1：确定是否存在早期损伤微血管内皮功能将预测 125I 后人类微血管脱落和视力丧失近距离放射治疗。为此，LSFG、光学相干断层扫描 (OCT) 和 OCT 血管造影 (OCT-A) 并将在接受 125I 近距离放射治疗的患者前瞻性队列中进行视功能测试用于脉络膜黑色素瘤。我们将测试早期眼部血流受损和闪烁光是否引起 LSFG 引起的血管舒张与随后的视力丧失和毛细血管脱落（通过 OCT-A 检测）相关。目的 2：测试选择性抑制内皮细胞中mitoROS的产生是否会阻止血液的早期减少辐射后毛细血管的流动和随后的损失。为了实现这一目标，遗传小鼠模型中的关键线粒体超氧化物产生的调节因子被抑制或过度表达将用于测试是否抑制内皮细胞中的线粒体活性氧可以防止视网膜血流的早期损伤，内皮功能障碍和随后的毛细血管脱落。拟议研究的预期结果是了解早期放射性视网膜病变的生物标志物以及对内皮细胞线粒体功能障碍在放射性视网膜病变中的作用的见解。我们的研究有促进开发针对放射相关视力丧失的一流靶向疗法的潜力。