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

项目概要/摘要 至少50%接受125I近距离放射治疗的葡萄膜黑色素瘤患者出现明显的视力丧失 治疗后3 - 5年内。广泛的血管病理已报告在正常的视网膜 2年或更长时间后，黑色素瘤周围。这些发现与公认的，但不完全一致。 微血管病由于微血管损伤而导致辐射相关的视力丧失的概念 在辐射期间。这导致在几年的滞后期后毛细血管逐渐丧失。如果这 假设是正确的，防止发展，或治疗，辐射诱导的内皮损伤， 视网膜微血管将减少毛细血管损失并挽救视力。不过，这种做法一直难以检验 因为微血管内皮功能障碍的早期指标还没有建立。 建议工程计划的目标是：促进及早发现、治疗和预防辐射- 相关的视力丧失。具体来说，我们预计1。检测早期内皮功能障碍的基础上减少 血流和对光闪烁的反应2.确定其是否预测随后的毛细损失，以及3. 确定辐射诱导内皮功能障碍的分子机制。我们将应用激光散斑 血流图（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中测试我们的假设：目标1：确定是否早期损害的 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） 将在接受125I近距离放射治疗的前瞻性患者队列中进行视觉功能检查 脉络膜黑色素瘤我们将测试是否早期损害眼血流和闪烁光诱导 LSFG的血管舒张与随后的视力丧失和毛细血管脱落相关（如通过OCT-A检测的）。目的 2：测试内皮中mitoROS产生的选择性抑制是否阻止血液循环的早期减少。 放射后毛细血管的流动和随后的损失。在这个目标中，遗传小鼠模型，其中关键 线粒体超氧化物产生的调节剂被抑制或过表达将用于测试是否 抑制内皮细胞中的线粒体ROS可保护视网膜血流免受早期损伤， 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作用的认识。我们的研究 有可能促进开发一流的针对辐射相关视力丧失的靶向疗法。

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.