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进行性化疗诱导的认知障碍（CICI， 通常称为“化学菌群”）。重要的是，没有预防/逆转CICI的策略。 化疗药物不能穿过血脑屏障，成熟神经元对化疗药物有抗性 剂.相比之下，内皮细胞暴露于最高浓度的这些药物，并且高度依赖于这些药物。 对它们的影响很敏感。我们发现，包括紫杉醇（PTX）在内的化疗药物可诱导 使微血管内皮细胞经历细胞衰老，这是一种常见的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即时调节和脑血流量的调节中起着重要作用。 通过神经血管耦合（NVC）和微循环网络的维持活动。这一切成功都 内皮功能对于健康的脑功能至关重要。本申请的中心假设是， 化学治疗剂诱导内皮衰老，这损害脑血流，促进 微血管稀疏和内皮依赖性神经血管偶联反应受损， 导致CICI的屏障完整性。这一假设将使用一种创新的小鼠模型进行测试：癌症- 用化疗药物紫杉醇（PTX）治疗的自由衰老报告小鼠，这使得 检测和选择性消除衰老细胞。具体目的：1）确定化疗如何诱导 内皮细胞衰老改变神经血管耦联反应和CBF。我们假设化疗 诱导内皮细胞衰老，损害内皮血管舒张功能， 内皮依赖性NVC反应和降低毛细血管密度，CBF失调。我们的预测， 基于这一假设，是通过基因操作或 可翻译的衰老清除疗法将恢复神经血管功能，并改善临床用 相关PTX协议。2)确定化疗诱导的内皮衰老如何影响微血管 密度的我们推测化疗诱导的内皮衰老损害了血管内皮细胞的维持， 微循环网络和/或损害内皮屏障功能，并且衰老细胞的消除将 增加微血管密度和恢复屏障功能，减轻神经炎症。3)怎么阻止我 化疗诱导的内皮衰老影响认知功能。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， 衰老细胞将阻止/延迟CICI的发展。我们的预期成果将产生一个综合的 了解化疗后微血管功能障碍的机制， 内皮衰老作为预防CICI的预防相关靶点。

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.