Chemotherapy-induced vascular cognitive impairment: role of endothelial senescence

项目摘要 许多癌症的长期幸存者经历了进行性化疗引起的认知障碍(CiCi， 通常被称为“化学脑损伤”)。重要的是，不存在预防/逆转CiCi的战略。 化疗药物不能穿过血脑屏障，成熟的神经元对化疗具有抵抗力 探员们。相比之下，内皮细胞暴露在这些药物的最高浓度下，并高度 对它们的影响很敏感。我们发现包括紫杉醇(PTX)在内的化疗药物可以诱导 脑微血管内皮细胞经历细胞衰老，是一种常见的DNA损伤反应。 内皮细胞在基础脑血流量的调节、脑血流量对神经元的瞬间调节中起着关键作用 通过神经血管偶联(NVC)和维持微循环网络的活动。这其中的每一个 内皮功能对健康的大脑功能至关重要。这个应用程序的中心假设是 化疗药物导致内皮细胞衰老，从而损害脑血流，促进 微血管疏松和内皮依赖性神经血管偶联反应和 栅栏诚信造就CiCi。这一假设将通过一种创新的小鼠模型进行验证：癌症- 用化疗药物紫杉醇(PTX)治疗的自由衰老报告鼠，它允许 检测和选择性消除衰老细胞。具体目标：1)阻止化疗如何诱发 内皮细胞的衰老改变了神经血管反应和脑血流。我们假设化疗 诱导内皮细胞衰老，从而损害内皮血管扩张功能 内皮依赖性NVC的反应和毛细血管密度降低，导致CBF失调。我们的预测， 基于这一假设，衰老的内皮细胞是通过基因操作还是通过 可翻译感觉神经溶解疗法可恢复小鼠神经血管功能并改善脑血流量 相关的PTX协议。2)检测化疗诱导的内皮细胞衰老对微血管的影响 密度。我们推测，化疗诱导的内皮细胞衰老损害了血管内皮细胞的维持 微循环网络和/或内皮屏障功能受损和衰老细胞的消除 增加脑微血管密度，恢复屏障功能，减轻神经炎症。3)阻止我如何 化疗诱导的内皮细胞衰老影响认知功能。我们假设PTX诱导的 微血管功能障碍导致多个认知领域的损害，并消除 衰老的细胞将阻止/延缓CII的发展。我们的预期结果将产生一个综合的 了解化疗后微血管功能障碍的机制并建立 内皮细胞衰老作为预防CiCi的翻译相关靶点。

Project Summary Many long-term survivors of cancer experience progressive chemotherapy-induced cognitive impairment (CICI, commonly referred to as "chemobrain"). Importantly, no strategies exist to prevent/reverse CICI. Chemotherapeutics do not cross the blood brain barrier and mature neurons are resistant to chemotherapeutic agents. In contrast, endothelial cells are exposed to the highest concentrations of these drugs and are highly sensitive to their effects. We discovered that chemotherapeutic drugs, including paclitaxel (PTX) induce cerebromicrovascular endothelial cells to undergo cellular senescence, a common DNA damage response. Endothelial cells play critical roles in regulation of basal CBF, moment-to-moment adjustment of CBF to neuronal activity via neurovascular coupling (NVC) and maintenance of the microcirculatory network. Each of these endothelial functions are critical for healthy brain function. The central hypothesis of this application is that chemotherapeutic agents induce endothelial senescence, which impairs cerebral blood flow, promote microvascular rarefaction and compromise endothelium-dependent neurovascular coupling responses and barrier integrity contributing to CICI. This hypothesis will be tested using an innovative mouse model: cancer- free senescence reporter mice treated with the chemotherapeutic drug paclitaxel (PTX), which allows the detection and selective elimination of senescent cells. Specific Aims: 1) Deter’mine how chemotherapy-induced endothelial sen’escence alters neurovascular coup’ling resp’onses and CBF. We postulate that chemotherapy induces senescence in endothelial cells, which impairs endothelial vasodilator function, compromises endothelium-dependent NVC responses and decreases capillary density, dysregulating CBF. Our prediction, based on this hypoth’esis, is that elimination of senesc’ent endothelial cells, through genetic manipulation or through translatable senolytic therapies w’ill restore neurovascular fun’ction and improve CBF in mice treated with clinically relevant PTX protocol. 2) Deter’mine how chemotherapy-induced endothelial sen’escence impacts microvascular density. We postulate that chemotherapy -induced endothelial senescence compromises the maintenance of the microcirculatory network and/or impairs endothelial barrier function and that elimination of senesc’ent cells w’ill increase cerebromicrovascular density and restore barrier function, attenuating neuroinflammation. 3) Deter’mine how chemotherapy-induced endothelial sen’escence impacts cognitive function. We postulate that PTX-induced microvascular dysfunction contribute to the impairment of multiple domains of cognition and that elimination of senescent cells will prevent/delay the development of CICI. Our expected outcomes will generate an integrated understanding of the mechanisms that underlie microvascular dysfunction after chemotherapy and establish endothelial senescence as a translationally relevant target for prevention of CICI.