Chemotherapy-induced vascular cognitive impairment: role of endothelial senescence

化疗引起的血管性认知障碍：内皮衰老的作用

基本信息

批准号：
10539312
负责人：
Anna Csiszar
金额：
$ 32.51万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539312
关键词：
Abbreviations Acceleration Address Adverse effects Affect Aging Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain Cancer Burden Cancer Patient Cancer Survivor Cell Aging Cells Cerebrovascular Circulation Clinical Cognition DNA Damage Data Detection Development Disease Endothelial Cells Endothelium Exposure to Functional Magnetic Resonance Imaging Ganciclovir Hemorrhage Impaired cognition Impairment Intervention Knowledge Laser Speckle Imaging Long-Term Survivors Maintenance Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of ovary Memory Microvascular Dysfunction Mission Modality Mus Neurons Outcome Oxidative Stress Paclitaxel Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Pre-Clinical Model Prevention Process Proteins Protocols documentation Public Health Publishing Quality of life Regulation Reporter Research Resistance Role Series Symptoms Testing Therapeutic Treatment outcome United States National Institutes of Health Vascular Cognitive Impairment Vascular Diseases Vasodilator Agents Work attentional control blood-brain barrier disruption cancer therapy cerebral microvasculature cerebrovascular chemobrain chemotherapeutic agent chemotherapy clinically relevant cognitive capacity cognitive function contrast imaging density executive function experience genetic manipulation improved innovation insight irradiation liposomal delivery loss of function malignant breast neoplasm mouse model negative affect neuroinflammation neurovascular neurovascular coupling novel novel therapeutic intervention pharmacologic prevent preventive intervention programs red fluorescent protein response senescence spatiotemporal two-photon vascular cognitive impairment and dementia

项目摘要

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.

项目概要许多癌症长期幸存者经历了化疗引起的进行性认知障碍（CICI，重要的是，不存在预防/逆转 CICI 的策略。化疗药物不能穿过血脑屏障，成熟的神经元对化疗药物有抵抗力相比之下，内皮细胞暴露于这些药物的浓度最高，并且浓度很高。我们发现化疗药物，包括紫杉醇（PTX）会诱导。脑微血管内皮细胞会经历细胞衰老，这是一种常见的 DNA 损伤反应。内皮细胞在基础CBF的调节、CBF对神经元的时刻调整中起着关键作用通过神经血管耦合 (NVC) 进行活动并维持微循环网络。内皮功能对于健康的大脑功能至关重要。该应用的中心假设是：化疗药物会引起内皮细胞衰老，从而损害脑血流，促进微血管稀疏并损害内皮依赖性神经血管耦合反应屏障完整性对 CICI 的贡献将使用创新的小鼠模型进行测试：癌症- 自由衰老记者用化疗药物紫杉醇（PTX）治疗小鼠，这使得检测和选择性消除衰老细胞具体目标： 1) 确定化疗如何诱导衰老细胞。内皮衰老会改变神经血管耦合反应和 CBF。诱导内皮细胞衰老，损害内皮血管舒张功能，损害内皮依赖性 NVC 反应并降低毛细血管密度，导致 CBF 失调。基于这个假设，通过基因操作或通过消除衰老的内皮细胞可转化的 senolytic 疗法将恢复神经血管功能并改善临床治疗小鼠的 CBF 相关的 PTX 方案 2) 确定化疗诱导的内皮衰老如何影响微血管。我们假设化疗引起的内皮衰老会损害细胞密度的维持。微循环网络和/或损害内皮屏障功能，消除衰老细胞将增加脑微血管密度并恢复屏障功能，减轻神经炎症 3) 确定如何。我们假设 PTX 诱导的内皮衰老会影响认知功能。微血管功能障碍会导致多个认知领域的损害以及消除衰老细胞将阻止/延缓 CICI 的发展，我们的预期结果将产生一个综合的结果。了解化疗后微血管功能障碍的机制并建立内皮衰老作为预防 CICI 的翻译相关目标。