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

项目摘要/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严重视力丧失 在治疗后3-5年内。据报道，在正常视网膜中存在广泛的血管病变。 黑色素瘤周围2年或更长时间。这些发现与公认的，但并不完全一致。 微血管病因微血管损伤而导致放射性相关视力丧失的概念 辐射时的内皮细胞。这导致在几年的滞后期后逐渐的毛细管丢失。如果这个 假说是正确的，防止或治疗放射性诱导的血管内皮损伤的发展 视网膜微血管将减少毛细血管丢失，挽救视力。然而，这种方法很难进行测试 因为微血管内皮细胞功能障碍的早期指标尚未建立。 拟议项目的目标是：促进及早发现、治疗和预防辐射- 相关的视力丧失。具体地说，我们期望1.根据减少的血管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.确定它是否预示着随后的毛细血管丢失和3. 确定辐射诱导的内皮功能障碍的分子机制。我们将应用激光散斑 无创、实时成像和测量眼部血流的血流图(LSFG) 受试者和小鼠来验证我们的中心假设，即辐射后内皮功能障碍是由 线粒体氧化应激，并可预测后续毛细血管脱落和 视力丧失。我们将在两个目标中检验我们的假设：目标1：确定早期的脑功能损害 微血管内皮功能将预测人类125I后微血管丢失和视力丧失 近距离放射治疗。为此，LSFG、光学相干断层扫描(OCT)和OCT-血管成像(OCT-A) 将在接受125I近距离放射治疗的前瞻性队列患者中进行视功能测试 脉络膜黑色素瘤。我们将测试早期眼血流障碍和闪光是否会导致 LSFG的血管扩张与随后的视力丧失和毛细血管脱落(如OCT-A检测到的)相关。目标 2：检测选择性抑制内皮细胞有丝分裂原生成是否能防止早期血液减少 辐射后毛细血管的流动和随后的丢失。在这个目标中，遗传小鼠模型中的关键 线粒体超氧化物生成被抑制或过度表达将被用来测试 抑制内皮细胞线粒体ROS可保护视网膜血流免受早期损害， 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记物。 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。我们的研究已经 促进开发一流的、有针对性的放射相关视力丧失疗法的潜力。

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.