Laser speckle flowgraphy as early indicator of microvasculopathy in radiation-induced cognitive decline

项目摘要/摘要 这项补充建议是我们的父代R01的扩展，以确定辐射诱导的介体 视力丧失和开发有效的基于机制的治疗方法。在父项目中，我们正在调查 视网膜微血管病变作为辐射诱发神经驱动因素的时程、机制及缓解 退化和功能丧失，有助于早期发现、预防和治疗与辐射相关的疾病 视网膜受损。在这里，我们认为放射治疗(RT)诱导的痴呆症是由相同的 视网膜内的微血管过程和分子机制以及视网膜激光散斑 血流图(LSFG)可作为一种早期检测方法。重要的是，血管认知 损害/痴呆症列在《NIH阿尔茨海默氏病编码定义》下的《相关痴呆 疾病及其相关痴呆症“。因此，本文提出的研究与NOT-AG-20-034直接相关。 高达90%的成年脑瘤幸存者会出现辐射导致的认知障碍。许多 RT的副作用被归因于由以下因素引起的微血管内皮损伤 RT过程中活性氧的过量产生和线粒体的损伤并导致内皮细胞 在一段时间内出现毛细血管功能障碍和丢失。然而，与放射治疗后视力丧失类似，概念 微血管病变是辐射相关痴呆的驱动因素尚未得到确凿的证实。这是在 部分原因是微血管内皮功能障碍的早期指标预测后来的认知能力下降 尚待确定。在我们的母公司R01中，我们使用激光散斑流动图(LSFG)作为一种新的非 侵入性方法用于检测早期RT诱导的微血管病变。在这里，我们建议部署试验性 我们亲本R01分析大脑结构和功能的方法和遗传模型。 拟议项目的目标是促进早期发现和治疗与RT相关的 痴呆症。具体地说，我们希望在小鼠身上开发非侵入性测试，以早期检测RT诱导的 基于血流改变的损伤，并确定早期内皮功能障碍是否预示着 随之而来的毛细血管密度降低和神经元功能障碍。我们还预计将确定 辐射致内皮细胞功能障碍的分子机制及其对认知功能损害的影响。 与亲本R01一样，LSFG的应用将使我们能够识别早期的“放射性内皮病变” 在毛细血管丧失之前，并测试分子机制，最终开发新的治疗方法。我们的中央 假设辐射后内皮细胞功能障碍是由线粒体氧化应激和 可以预测随后毛细血管脱落和神经元损伤的严重程度。利用我们的 成像方案，我们将(1)确定微血管内皮功能的早期损害 预测放疗后微血管丢失和神经元功能障碍，以及(2)测试选择性抑制 内皮细胞产生mitoROS可防止放疗后早期血流量减少和毛细血管丢失。

PROJECT SUMMARY/ABSTRACT This supplemental proposal is an extension of our parent R01 to identify the mediators of radiation-induced vision loss and to develop effective mechanism-based therapies. In the parent project, we are investigating the time course, mechanism and mitigation of retinal microvasculopathy as a driver of radiation-induced neural degeneration and functional loss to facilitate earlier detection, prevention and treatment of radiation-associated retinal damage. Here, we propose that radiation therapy (RT)-induced dementia is driven by the same microvascular processes and molecular mechanisms as within the retina and that retinal laser speckle flowgraphy (LSFG) can be used as an early detection strategy. Importantly, Vascular Cognitive Impairment/Dementia is listed under “Related Dementias” under the “NIH Coding definitions for Alzheimer's disease and its related Dementias”. Thus, the research proposed herein is directly relevant to NOT-AG-20-034. Radiation-induced cognitive impairment occurs in up to 90% of adult survivors of brain tumors. Many adverse side effects of RT have been attributed to damage of microvascular endothelium that is initiated by excessive production of reactive oxygen species and mitochondrial injury during RT and leads to endothelial dysfunction and loss of capillaries over a period of years. However, similar to vision loss after RT, the concept that microangiopathy is a driver of radiation-related dementia has not been conclusively established. This is in part because early indicators of microvascular endothelial dysfunction that predict later cognitive decline have yet to be established. In our parent R01, we are using laser speckle flowgraphy (LSFG) as a novel non- invasive modality to detect early RT-induced microangiopathy. Here, we propose to deploy the experimental approaches and genetic models of our parent R01 to analyze cerebral structure and function. The objectives of the proposed project are to facilitate earlier detection and treatment of RT-associated dementia. Specifically, we expect to develop non-invasive tests in mice for the early detection of RT-induced injury based on altered blood flow and determine whether early endothelial dysfunction is predictive of a subsequent reduction in capillary density and neuronal dysfunction. We also anticipate identifying the molecular mechanism of radiation-induced endothelial dysfunction and its impact on cognitive impairment. As in the parent R01, the application of LSFG will enable us to identify early “radiation endotheliopathy” before capillary loss, and to test molecular mechanisms to ultimately develop novel therapies. Our central hypothesis is that post-radiation endothelial dysfunction is driven by mitochondrial oxidative stress and is predictive of the severity of subsequent capillary dropout and neuronal damage. Capitalizing on our imaging protocols, we will (1) establish whether early impairment of the microvascular endothelial function predicts microvessel dropout and neuronal dysfunction after RT and (2) test whether selective inhibition of mitoROS production in endothelium prevents the early reduction of blood flow and loss of capillaries after RT.