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：
10323272
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/10323272
关键词：
Abbreviations Address Adverse effects Affect Aging Attenuated Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain Cancer Burden Cancer Model Cancer Patient Cancer Survivor Cell Aging Cells Cerebrovascular Circulation Chimeric Proteins Clinical Cognition Consequentialism DNA Damage Data Detection Development Disease Endothelial Cells Endothelium Exposure to Functional Magnetic Resonance Imaging Ganciclovir Hemorrhage Image Impaired cognition Impairment Intervention Knowledge Laser Speckle Imaging Long-Term Survivors Maintenance 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 Pharmacology Phenotype Play Pre-Clinical Model Prevention Process Protocols documentation Public Health Publishing Quality of life Regulation Reporter Research Resistance Role Series Symptoms Testing Treatment outcome United States National Institutes of Health Vascular Cognitive Impairment Vascular Diseases Vasodilator Agents Work attentional control base blood-brain barrier disruption cancer therapy cerebral microvasculature cerebrovascular chemobrain chemotherapeutic agent chemotherapy clinically relevant cognitive capacity cognitive development cognitive function 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 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.

项目摘要癌症的许多长期生存经历了进行性化疗引起的认知障碍（CICI，通常称为“ Chemobrain”）。重要的是，没有防止/逆转CICI的策略。化学疗法不会越过血脑屏障，并且成熟的神经元对化学治疗性具有抗性代理商。相反，内皮细胞暴露于这些药物的最高浓度，高度对它们的影响敏感。我们发现化学治疗药物，包括紫杉醇（PTX）的影响脑血管内皮细胞会经历细胞感应，这是一种常见的DNA损伤反应。内皮细胞在调节基本CBF的调节中起关键作用通过神经血管耦合（NVC）和微循环网络的维护活动。每个内皮功能对于健康的大脑功能至关重要。该应用程序的中心假设是化学治疗剂诱导内皮感应，从而损害脑血流，促进微血管稀疏和妥协的内皮依赖性神经血管耦合反应和有助于CICI的障碍完整性。该假设将使用创新的小鼠模型进行检验：癌症 - 用化学治疗药物紫杉醇（PTX）处理的自由感应记者小鼠，该小鼠允许检测和选择性消除感觉细胞。具体目的：1）阻止化学疗法诱导的金属内皮鼻enscence改变了神经血管couty的反应和CBF。我们假设化学疗法诱导内皮细胞的感受，会损害内皮血管扩张剂的功能，这会损害依赖内皮的NVC反应并下降毛细管密度，CBF失调。我们的预测，基于这种假设，是通过基因操纵或通过可翻译的塞溶性疗法会恢复神经血管的乐趣，并改善接受临床治疗的小鼠的CBF 相关的PTX协议。 2）阻止化学疗法诱导的内皮衰变如何影响微血管密度。我们假设化学疗法诱导的内皮感应损害了维持微循环网络和/或损害内皮屏障功能，并消除senesc'ent细胞。增加脑血管密度并恢复屏障功能，减轻神经炎症。 3）阻止“如何” 化学疗法引起的内皮衰变会影响认知功能。我们假设PTX引起的微血管功能障碍有助于多个认知领域的损害，并消除感觉细胞将阻止/延迟CICI的发展。我们的预期结果将产生一个集成的了解化学疗法后微血管功能障碍的机制，并建立内皮感应是预防CICI的翻译相关靶标。