Radiation-induced astrocyte dysfunction and cognitive decline

辐射引起的星形胶质细胞功能障碍和认知能力下降

• 批准号: 10059271
• 负责人: ZOLTAN Istvan UNGVARI
• 金额: $ 34.29万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059271
• 关键词: Acids; Aftercare; Astrocytes; Biochemistry; Brain; Brain Injuries; Brain Mass; Brain Neoplasms; Cancer Survivor; Cell Aging; Cells; Cerebrovascular Circulation; Cerebrovascular system; Cerebrum; Cognition; Cranial Irradiation; DNA; DNA Damage; Data; Dementia; Diagnosis; Disseminated Malignant Neoplasm; Dose; Eicosanoids; Energy Metabolism; Etiology; Functional disorder; Gene Expression; Goals; Human; Hyperemia; Imaging Techniques; Impaired cognition; Impairment; In Vitro; Incidence; Intervention; Laser Speckle Imaging; Learning; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measurement; Mediating; Mediator of activation protein; Memory; Metastatic malignant neoplasm to brain; Mitotic; Mus; Neurologic Symptoms; Neurons; Newly Diagnosed; Outcome; Pathogenicity; Pathway interactions; Patients; Pharmacology; Phenotype; Play; Prevention; Process; Production; Prostaglandins; Proteomics; Publishing; Radiation; Radiation Tolerance; Radiation induced damage; Regulation; Role; Signal Transduction; Site; Testing; Time; Up-Regulation; Vascular blood supply; Vasodilation; Vasodilator Agents; Work; aging brain; base; brain health; cellular imaging; cerebral microvasculature; clinically relevant; cognitive function; effective intervention; experience; genetic manipulation; improved; irradiation; lipid mediator; liquid chromatography mass spectrometry; malignant breast neoplasm; mouse model; neurovascular; neurovascular coupling; neurovascular unit; novel; prevent; programs; radioresistant; response; senescence; side effect; tool

Whole brain irradiation (WBI) leads to progressive dementia in ~50% of brain tumor patients who survive long- term after treatment, at least in part, due to dysregulation of CBF. Although the specific mechanisms for WBI- induced deceases in CBF and cognitive decline are not yet known, there is increasing evidence that alterations of the neurovascular unit play a crucial role. The objective of this proposal is to elucidate the mechanistic role of irradiation-induced astrocyte dysfunction in cognitive impairment. The central hypothesis is that irradiation causes astrocyte senescence and subsequent dysfunction, altering the production of vasodilator mediators and impairing neurovascular coupling (NVC) responses. The resulting neurovascular dysfunction contributes to decline in CBF and cognitive impairments. The proposed work is novel in that it will be the first to demonstrate that radiation-induced astrocyte senescence is a key driver of the effects of WBI on the brain. The results will likely identify specific mechanisms and reveal potential therapies that are capable of improving cerebral blood supply and restoring learning and memory. The following aims are proposed: 1) Elucidate the cellular mechanisms underlying WBI-induced impairment of NVC responses. The working hypothesis is that WBI impairs both eicosanoid-mediated and purinergic components of NVC responses. To test this hypothesis in a clinically relevant mouse model of WBI, pathways contributing to NVC responses will be assessed using laser speckle contrast imaging, pharmacological tools and LC/MS/MS-based measurement of gliotransmitter release. The impact of pharmacological up-regulation of NVC responses on cognitive function of WBI-treated mice will be determined. 2) Determine how irradiation-induced senescence alters astrocyte function and phenotype. It is predicted that irradiation induces senescence in astrocytes, which impairs cellular energy metabolism and the production/release of ATP and alters the cellular secretory profile, dysregulating the synthesis of vasoactive lipid mediators. To test these hypotheses senescent astrocytes will be isolated from WBI-treated mice and primary human astrocyte cultures will be irradiated in vitro. We will combine advanced cellular imaging techniques and cutting-edge proteomics and biochemistry to investigate cellular energetics, gene expression and secretome signatures, the regulation of ATP release and the synthesis of lipid mediators. 3) Determine whether elimination of senescent cells improves NVC and cognitive function in WBI-treated mice. It is hypothesized that activation of p16-dependent cellular senescence programs is responsible for WBI-induced neurovascular dysfunction and cognitive impairment. It is expected that elimination of senescent cells, either through genetic manipulation (p16-3MR mouse model) or by pharmacological means will restore neurovascular function and improve cognition in WBI-treated mice. Together, the proposed studies will identify a fundamental mechanism governing WBI-related neurovascular dysfunction eventually leading to cognitive impairment.

整个大脑辐照（WBI）导致约50％的脑肿瘤患者的进行性痴呆 治疗后的期限至少部分由于CBF的失调。虽然WBI的特定机制 尚不清楚CBF诱发的衰落和认知能力下降，越来越多的证据表明改变的变化 神经血管单元起着至关重要的作用。该提案的目的是阐明 辐照引起的星形胶质细胞功能障碍在认知障碍中。中心假设是辐照 导致星形胶质细胞衰老和随后的功能障碍，改变血管扩张剂介质的产生 并损害神经血管耦合（NVC）反应。由此产生的神经血管功能障碍有助于 CBF和认知障碍的下降。拟议的工作是新颖的，因为它将是第一个证明 辐射引起的星形胶质细胞衰老是WBI对大脑作用的关键驱动力。结果将 可能识别特定机制并揭示能够改善脑血液的潜在疗法 供应和恢复学习和记忆。提出了以下目的：1）阐明细胞 WBI诱导的NVC响应损害的机制。工作的假设是WBI都会损害 NVC响应的eicosanoid介导的和嘌呤能成分。在临床上检验该假设 WBI的相关鼠标模型，将使用激光斑点评估有助于NVC响应的途径 对比成像，药理学工具和基于LC/MS/MS/MS/MS/MS/MS的测量。这 NVC反应的药理上调对WBI治疗小鼠认知功能的影响将是 决定。 2）确定辐射诱导的衰老如何改变星形胶质细胞功能和表型。这是 预测辐射会诱导星形胶质细胞衰老，这会损害细胞能量代谢和 ATP的生产/释放并改变细胞分泌概况，使血管活性的合成失调 脂质介体。为了检验这些假设，衰老的星形胶质细胞将从WBI处理的小鼠中分离出来， 原发性人星形胶质细胞培养物将在体外得到照射。我们将结合先进的蜂窝成像 技术和尖端蛋白质组学和生物化学，以研究细胞能量学，基因表达和 分泌的特征，ATP释放的调节和脂质介质的合成。 3）确定 消除衰老细胞是否可以改善WBI治疗小鼠的NVC和认知功能。它是假设的 p16依赖性细胞衰老程序的激活负责WBI诱导的神经血管 功能障碍和认知障碍。预计消除衰老细胞是通过遗传 操纵（P16-3MR小鼠模型）或通过药理学手段将恢复神经血管功能和 改善WBI治疗小鼠的认知。拟议的研究将共同​​确定基本机制 管理与WBI相关的神经血管功能障碍最终导致认知障碍。